NM_144670.6(A2ML1):c.2145del (p.Phe715fs) AND not provided

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Jan 8, 2024
Review status:: criteria provided, conflicting classifications

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000797125.8

Allele description [Variation Report for NM_144670.6(A2ML1):c.2145del (p.Phe715fs)]

NM_144670.6(A2ML1):c.2145del (p.Phe715fs)

Gene:

A2ML1:alpha-2-macroglobulin like 1 [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

12p13.31

Genomic location:

Preferred name:

NM_144670.6(A2ML1):c.2145del (p.Phe715fs)

HGVS:

NC_000012.12:g.8850185del
NG_042857.1:g.32714del
NM_001282424.3:c.672del
NM_144670.5:c.2145delT
NM_144670.6:c.2145delMANE SELECT
NP_001269353.2:p.Phe224fs
NP_653271.3:p.Phe715fs
NC_000012.11:g.9002778del
NC_000012.11:g.9002781del
NM_144670.4:c.2145del
NM_144670.4:c.2145delT

Protein change:

F224fs

Links:

dbSNP: rs759217676

NCBI 1000 Genomes Browser:

rs759217676

Molecular consequence:

NM_001282424.3:c.672del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_144670.6:c.2145del - frameshift variant - [Sequence Ontology: SO:0001589]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000936667	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jan 8, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002008633	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Likely benign (Jul 31, 2020)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000936667

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jan 8, 2024)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV002008633

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Likely benign
(Jul 31, 2020)

germline

clinical testing

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240-242.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Invitae, SCV000936667.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

This sequence change creates a premature translational stop signal (p.Phe715Leufs*52) in the A2ML1 gene. It is expected to result in an absent or disrupted protein product. However, the current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in A2ML1 cause disease. This variant is present in population databases (rs759217676, gnomAD 0.05%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with A2ML1-related conditions. ClinVar contains an entry for this variant (Variation ID: 643431). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From GeneDx, SCV002008633.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Mar 5, 2024

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