12-8843160-A-G

Position:

chr12-8843160-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_144670.6(A2ML1):c.1275A>G(p.Val425=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0883 in 1,613,954 control chromosomes in the GnomAD database, including 7,298 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. V425V) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.066 ( 494 hom., cov: 32)

Exomes 𝑓: 0.091 ( 6804 hom. )

Consequence

A2ML1
NM_144670.6 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -0.208

Variant links:

Genes affected

A2ML1 (HGNC:23336): (alpha-2-macroglobulin like 1) This gene encodes a member of the alpha-macroglobulin superfamily. The encoded protein is thought to be an N-glycosylated monomeric protein that acts as an inhibitor of several proteases. It has been shown to form covalent interactions with proteases, and has been reported as the p170 antigen recognized by autoantibodies in the autoimmune disease paraneoplastic pemphigus (PNP; PMID:20805888). Mutations in these gene have also been associated with some cases of Noonan syndrome (NS; PMID:24939586) as well as some cases of otitis media (PMID:26121085). Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Aug 2015]

A2ML1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.84).

BP6

Variant 12-8843160-A-G is Benign according to our data. Variant chr12-8843160-A-G is described in ClinVar as [Benign]. Clinvar id is 384677.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-8843160-A-G is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-0.208 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0975 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
A2ML1	NM_144670.6 linkuse as main transcript	c.1275A>G	p.Val425=	synonymous_variant	12/36	ENST00000299698.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
A2ML1	ENST00000299698.12 linkuse as main transcript	c.1275A>G	p.Val425=	synonymous_variant	12/36	1	NM_144670.6	P1	A8K2U0-1

Frequencies

GnomAD3 genomes

AF:

0.0660

AC:

10048

AN:

152176

Hom.:

494

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0179

Gnomad AMI

AF:

0.0164

Gnomad AMR

AF:

0.0739

Gnomad ASJ

AF:

0.139

Gnomad EAS

AF:

0.000577

Gnomad SAS

AF:

0.0252

Gnomad FIN

AF:

0.0547

Gnomad MID

AF:

0.101

Gnomad NFE

AF:

0.0994

Gnomad OTH

AF:

0.0847

GnomAD3 exomes

AF:

0.0711

AC:

17747

AN:

249524

Hom.:

820

AF XY:

0.0716

AC XY:

9692

AN XY:

135382

show subpopulations

Gnomad AFR exome

AF:

0.0148

Gnomad AMR exome

AF:

0.0565

Gnomad ASJ exome

AF:

0.146

Gnomad EAS exome

AF:

0.000111

Gnomad SAS exome

AF:

0.0316

Gnomad FIN exome

AF:

0.0580

Gnomad NFE exome

AF:

0.100

Gnomad OTH exome

AF:

0.0921

GnomAD4 exome

AF:

0.0906

AC:

132401

AN:

1461660

Hom.:

6804

Cov.:

AF XY:

0.0894

AC XY:

65034

AN XY:

727160

show subpopulations

Gnomad4 AFR exome

AF:

0.0145

Gnomad4 AMR exome

AF:

0.0582

Gnomad4 ASJ exome

AF:

0.140

Gnomad4 EAS exome

AF:

0.000151

Gnomad4 SAS exome

AF:

0.0329

Gnomad4 FIN exome

AF:

0.0603

Gnomad4 NFE exome

AF:

0.102

Gnomad4 OTH exome

AF:

0.0880

GnomAD4 genome

AF:

0.0660

AC:

10044

AN:

152294

Hom.:

494

Cov.:

AF XY:

0.0626

AC XY:

4663

AN XY:

74456

show subpopulations

Gnomad4 AFR

AF:

0.0179

Gnomad4 AMR

AF:

0.0738

Gnomad4 ASJ

AF:

0.139

Gnomad4 EAS

AF:

0.000579

Gnomad4 SAS

AF:

0.0251

Gnomad4 FIN

AF:

0.0547

Gnomad4 NFE

AF:

0.0995

Gnomad4 OTH

AF:

0.0838

Alfa

AF:

0.0914

Hom.:

1230

Bravo

AF:

0.0650

Asia WGS

AF:

0.0130

AC:

AN:

3478

EpiCase

AF:

0.0984

EpiControl

AF:

0.101

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 29, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 06, 2017	Variant summary: The A2ML1 c.1275A>G (p.Val425Val) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. Mutation taster predicts a benign outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant may affect ESE site of SRp55. However, these predictions have yet to be confirmed by functional studies. This variant was found in 8489/120660 control chromosomes (396 homozygotes) from ExAC at a frequency of 0.0703547, which is approximately 17589 times the estimated maximal expected allele frequency of a pathogenic A2ML1 variant (0.000004), thus it is a benign common polymorphism. In addition, a clinical diagnostic laboratory (via ClinVar) has classified this variant as benign. It has also been published as a benign SNP in literature (Justino_2014/2015). Taken together, this variant is classified as benign. -

not specified

Benign:2

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

4.4

DANN

Benign

0.66

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over