12-8851954-G-A

Position:

chr12-8851954-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_144670.6(A2ML1):c.2405G>A(p.Arg802His) variant causes a missense change. The variant allele was found at a frequency of 0.000458 in 1,614,158 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00038 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00047 ( 4 hom. )

Consequence

A2ML1
NM_144670.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:5

Conservation

PhyloP100: 4.47

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 -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.03913936).

BS2

High AC in GnomAd4 at 58 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
A2ML1	NM_144670.6 link	c.2405G>A	p.Arg802His	missense_variant	19/36	ENST00000299698.12	NP_653271.3	B3KVV6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
A2ML1	ENST00000299698.12 link	c.2405G>A	p.Arg802His	missense_variant	19/36	1	NM_144670.6	ENSP00000299698.7	A8K2U0-1
A2ML1	ENST00000541459.5 link	c.1055G>A	p.Arg352His	missense_variant	8/25	2		ENSP00000443174.1	H0YGG5
A2ML1	ENST00000539547.5 link	c.932G>A	p.Arg311His	missense_variant	8/25	2		ENSP00000438292.1	A8K2U0-2

Frequencies

GnomAD3 genomes

AF:

0.000381

AC:

AN:

152154

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00461

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00290

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000353

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000657

AC:

164

AN:

249558

Hom.:

AF XY:

0.000687

AC XY:

AN XY:

135398

show subpopulations

Gnomad AFR exome

AF:

0.0000646

Gnomad AMR exome

AF:

0.0000579

Gnomad ASJ exome

AF:

0.00735

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00154

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000335

Gnomad OTH exome

AF:

0.000330

GnomAD4 exome

AF:

0.000467

AC:

682

AN:

1461886

Hom.:

Cov.:

AF XY:

0.000494

AC XY:

359

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.000119

Gnomad4 AMR exome

AF:

0.0000894

Gnomad4 ASJ exome

AF:

0.00643

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00151

Gnomad4 FIN exome

AF:

0.0000749

Gnomad4 NFE exome

AF:

0.000279

Gnomad4 OTH exome

AF:

0.000828

GnomAD4 genome

AF:

0.000381

AC:

AN:

152272

Hom.:

Cov.:

AF XY:

0.000376

AC XY:

AN XY:

74456

show subpopulations

Gnomad4 AFR

AF:

0.0000722

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00461

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00290

Gnomad4 FIN

AF:

0.0000942

Gnomad4 NFE

AF:

0.000353

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000574

Hom.:

Bravo

AF:

0.000397

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000482

AC:

ExAC

AF:

0.000670

AC:

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.000327

EpiControl

AF:

0.000415

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:1

Uncertain significance, no assertion criteria provided	literature only	OMIM	Mar 01, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2025	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Department of Human Genetics, University Hospital Magdeburg	Jul 09, 2020	This variant has been previously published as a causal variant for a disorder resembling Noonan syndrome by Vissers et al (2015). The allele frequency of this variant in gnomAD is greater than expected for Noonan syndrome (5.98e-4) (BS1). In-silico prediction yields consistent gene function affecting result (PP3). The variant was once found in a patient harbouring a known causal RAF1 variant and once in a patient harbouring a known causal MAP2K1 variant, fully explaining the phenotypes in both patients (BP5). Additionally, the variant was found to be inherited by the index patient's unaffected father in one case (BS2). -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 21, 2021	Variant summary: A2ML1 c.2405G>A (p.Arg802His) results in a non-conservative amino acid change located in the Alpha-2-macroglobulin domain (IPR001599) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00066 in 249558 control chromosomes, predominantly at a frequency of 0.0015 within the South Asian subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 375 fold of the estimated maximal expected allele frequency for a pathogenic variant in A2ML1 causing Noonan Syndrome phenotype (4e-06), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. c.2405G>A has been reported in the literature in individuals affected with Noonan Syndrome, including one de novo occurrence (Vissers_2015, Tidyman_2016, Brinkmann_2020). These data do not allow any conclusion about variant significance. Co-occurrences with other pathogenic variants have been reported (RAF1 c.770C>T , p.Ser257Leu; MAP2K1 c.275T>G, p.Leu92Arg) (Brinkmann_2020), providing supporting evidence for a benign role. At least one publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (Vissers_2015). Three ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=2) and likely benign (n=1). Based on the evidence outlined above, the variant was classified as likely benign. -

A2ML1-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 21, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Noonan syndrome

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Service de Génétique Moléculaire, Hôpital Robert Debré

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.18

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.10

T;T;.

Eigen

Uncertain

0.57

Eigen_PC

Uncertain

0.46

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.88

D;D;D

M_CAP

Pathogenic

0.73

MetaRNN

Benign

0.039

T;T;T

MetaSVM

Benign

-0.59

MutationAssessor

Pathogenic

3.7

H;.;.

PrimateAI

Uncertain

0.52

PROVEAN

Uncertain

-4.1

D;D;D

REVEL

Pathogenic

0.76

Sift

Uncertain

0.0020

D;D;D

Sift4G

Uncertain

0.0030

D;D;D

Polyphen

1.0

D;.;.

Vest4

0.84

MVP

0.47

MPC

0.59

ClinPred

0.18

GERP RS

3.9

Varity_R

0.25

gMVP

0.78

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