12-8838341-C-A

Position:

chr12-8838341-C-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_144670.6(A2ML1):c.861C>A(p.Asp287Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0099 in 1,612,544 control chromosomes in the GnomAD database, including 93 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0070 ( 8 hom., cov: 32)

Exomes 𝑓: 0.010 ( 85 hom. )

Consequence

A2ML1
NM_144670.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6O:1

Conservation

PhyloP100: -0.0420

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:

A2ML1 (HGNC:):

A2ML1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.00356704).

BP6

Variant 12-8838341-C-A is Benign according to our data. Variant chr12-8838341-C-A is described in ClinVar as [Benign]. Clinvar id is 120256.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-8838341-C-A is described in Lovd as [Benign].

BS2

High AC in GnomAd4 at 1071 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
A2ML1	NM_144670.6 linkuse as main transcript	c.861C>A	p.Asp287Glu	missense_variant	9/36	ENST00000299698.12	NP_653271.3	B3KVV6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
A2ML1	ENST00000299698.12 linkuse as main transcript	c.861C>A	p.Asp287Glu	missense_variant	9/36	1	NM_144670.6	ENSP00000299698.7		A8K2U0-1

Frequencies

GnomAD3 genomes

AF:

0.00703

AC:

1070

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00164

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00557

Gnomad ASJ

AF:

0.0311

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.00546

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0107

Gnomad OTH

AF:

0.00574

GnomAD3 exomes

AF:

0.00770

AC:

1916

AN:

248948

Hom.:

AF XY:

0.00768

AC XY:

1037

AN XY:

135048

show subpopulations

Gnomad AFR exome

AF:

0.00174

Gnomad AMR exome

AF:

0.00380

Gnomad ASJ exome

AF:

0.0306

Gnomad EAS exome

AF:

0.0000557

Gnomad SAS exome

AF:

0.00151

Gnomad FIN exome

AF:

0.00557

Gnomad NFE exome

AF:

0.0110

Gnomad OTH exome

AF:

0.00630

GnomAD4 exome

AF:

0.0102

AC:

14894

AN:

1460254

Hom.:

Cov.:

AF XY:

0.00988

AC XY:

7176

AN XY:

726430

show subpopulations

Gnomad4 AFR exome

AF:

0.00182

Gnomad4 AMR exome

AF:

0.00398

Gnomad4 ASJ exome

AF:

0.0278

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00164

Gnomad4 FIN exome

AF:

0.00547

Gnomad4 NFE exome

AF:

0.0115

Gnomad4 OTH exome

AF:

0.0107

GnomAD4 genome

AF:

0.00703

AC:

1071

AN:

152290

Hom.:

Cov.:

AF XY:

0.00655

AC XY:

488

AN XY:

74470

show subpopulations

Gnomad4 AFR

AF:

0.00164

Gnomad4 AMR

AF:

0.00556

Gnomad4 ASJ

AF:

0.0311

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00145

Gnomad4 FIN

AF:

0.00546

Gnomad4 NFE

AF:

0.0107

Gnomad4 OTH

AF:

0.00568

Alfa

AF:

0.00976

Hom.:

Bravo

AF:

0.00718

TwinsUK

AF:

0.0108

AC:

ALSPAC

AF:

0.0114

AC:

ESP6500AA

AF:

0.00154

AC:

ESP6500EA

AF:

0.0142

AC:

118

ExAC

AF:

0.00744

AC:

899

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.00922

EpiControl

AF:

0.0108

ClinVar

Significance: Benign

Submissions summary: Benign:6Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4Other:1

not provided, no classification provided	literature only	Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP)	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
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.861C>A (p.Asp287Glu) variant involves the alteration of a non-conserved nucleotide. 2/3 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 898/120478 control chromosomes (5 homozygotes) from ExAC, predominantly observed in the European (Non-Finnish) subpopulation at a frequency of 0.011976 (798/66632). This frequency is about 2994 times the estimated maximal expected allele frequency of a pathogenic A2ML1 variant (0.000004), suggesting this is likely a benign polymorphism found primarily in the populations of European (Non-Finnish) origin. In addition, multiple clinical diagnostic laboratories have classified this variant as benign. Taken together, this variant is classified as benign. -
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	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:2

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

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.53

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.019

Eigen

Benign

0.075

Eigen_PC

Benign

0.072

FATHMM_MKL

Benign

0.65

LIST_S2

Benign

0.57

MetaRNN

Benign

0.0036

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.3

PrimateAI

Benign

0.39

PROVEAN

Benign

-2.0

REVEL

Benign

0.034

Sift

Benign

0.040

Sift4G

Benign

0.16

Polyphen

0.78

Vest4

0.32

MutPred

0.29

Gain of sheet (P = 0.0827);

MVP

0.17

MPC

0.19

ClinPred

0.0050

GERP RS

2.9

Varity_R

0.13

gMVP

0.75

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