12-8857183-C-T

Position:

chr12-8857183-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_144670.6(A2ML1):c.2868C>T(p.Ala956=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0473 in 1,612,308 control chromosomes in the GnomAD database, including 2,274 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.037 ( 174 hom., cov: 30)

Exomes 𝑓: 0.048 ( 2100 hom. )

Consequence

A2ML1
NM_144670.6 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -0.631

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 -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.25).

BP6

Variant 12-8857183-C-T is Benign according to our data. Variant chr12-8857183-C-T is described in ClinVar as [Benign]. Clinvar id is 384725.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-8857183-C-T is described in Lovd as [Likely_benign]. Variant chr12-8857183-C-T is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-0.631 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0522 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
A2ML1	NM_144670.6 linkuse as main transcript	c.2868C>T	p.Ala956=	synonymous_variant	24/36	ENST00000299698.12	NP_653271.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
A2ML1	ENST00000299698.12 linkuse as main transcript	c.2868C>T	p.Ala956=	synonymous_variant	24/36	1	NM_144670.6	ENSP00000299698	P1	A8K2U0-1
A2ML1	ENST00000541459.5 linkuse as main transcript	c.1518C>T	p.Ala506=	synonymous_variant	13/25	2		ENSP00000443174
A2ML1	ENST00000539547.5 linkuse as main transcript	c.1395C>T	p.Ala465=	synonymous_variant	13/25	2		ENSP00000438292		A8K2U0-2

Frequencies

GnomAD3 genomes

AF:

0.0371

AC:

5638

AN:

152044

Hom.:

173

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00930

Gnomad AMI

AF:

0.0197

Gnomad AMR

AF:

0.0165

Gnomad ASJ

AF:

0.0127

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0135

Gnomad FIN

AF:

0.110

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.0536

Gnomad OTH

AF:

0.0249

GnomAD3 exomes

AF:

0.0379

AC:

9448

AN:

249278

Hom.:

304

AF XY:

0.0388

AC XY:

5245

AN XY:

135222

show subpopulations

Gnomad AFR exome

AF:

0.00756

Gnomad AMR exome

AF:

0.0142

Gnomad ASJ exome

AF:

0.0114

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0152

Gnomad FIN exome

AF:

0.110

Gnomad NFE exome

AF:

0.0501

Gnomad OTH exome

AF:

0.0385

GnomAD4 exome

AF:

0.0484

AC:

70658

AN:

1460146

Hom.:

2100

Cov.:

AF XY:

0.0475

AC XY:

34500

AN XY:

726380

show subpopulations

Gnomad4 AFR exome

AF:

0.00568

Gnomad4 AMR exome

AF:

0.0145

Gnomad4 ASJ exome

AF:

0.0134

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0149

Gnomad4 FIN exome

AF:

0.105

Gnomad4 NFE exome

AF:

0.0542

Gnomad4 OTH exome

AF:

0.0382

GnomAD4 genome

AF:

0.0370

AC:

5637

AN:

152162

Hom.:

174

Cov.:

AF XY:

0.0382

AC XY:

2844

AN XY:

74370

show subpopulations

Gnomad4 AFR

AF:

0.00927

Gnomad4 AMR

AF:

0.0165

Gnomad4 ASJ

AF:

0.0127

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.0137

Gnomad4 FIN

AF:

0.110

Gnomad4 NFE

AF:

0.0536

Gnomad4 OTH

AF:

0.0246

Alfa

AF:

0.0447

Hom.:

111

Bravo

AF:

0.0295

Asia WGS

AF:

0.00837

AC:

AN:

3478

EpiCase

AF:

0.0475

EpiControl

AF:

0.0484

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 30, 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 07, 2017	Variant summary: The A2ML1 c.2868C>T (p.Ala956Ala) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. Mutation taster predicts a polymorphism outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant may affect binding of multiple ESE sites. However, these predictions have yet to be confirmed by functional studies. This variant was found in 4589/120498 control chromosomes (135 homozygotes) at a frequency of 0.0380836, which is approximately 9521 times the estimated maximal expected allele frequency of a pathogenic A2ML1 variant (0.000004), suggesting this variant is likely a benign polymorphism. In addition, multiple clinical diagnostic laboratories (via ClinVar) have classified this variant as benign. It has also been reported as a non-pathogenic variant in literature (Vissers_2015). Taken together, this variant is classified as benign. -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not specified

Benign:2

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Otitis media, susceptibility to

Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Nov 22, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.25

CADD

Benign

6.3

DANN

Benign

0.60

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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