12-8851801-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_144670.6(A2ML1):c.2252C>T(p.Ala751Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00171 in 1,614,050 control chromosomes in the GnomAD database, including 53 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A751T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0090 ( 26 hom., cov: 32)

Exomes 𝑓: 0.00095 ( 27 hom. )

Consequence

A2ML1
NM_144670.6 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -0.289

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0037553012).

BP6

Variant 12-8851801-C-T is Benign according to our data. Variant chr12-8851801-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 241890.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-8851801-C-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00904 (1376/152238) while in subpopulation AFR AF= 0.031 (1286/41530). AF 95% confidence interval is 0.0296. There are 26 homozygotes in gnomad4. There are 655 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 1376 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
A2ML1	NM_144670.6 link	c.2252C>T	p.Ala751Val	missense_variant	Exon 19 of 36	ENST00000299698.12	NP_653271.3	B3KVV6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
A2ML1	ENST00000299698.12 link	c.2252C>T	p.Ala751Val	missense_variant	Exon 19 of 36	1	NM_144670.6	ENSP00000299698.7	A8K2U0-1
A2ML1	ENST00000541459.5 link	c.902C>T	p.Ala301Val	missense_variant	Exon 8 of 25	2		ENSP00000443174.1	H0YGG5
A2ML1	ENST00000539547.5 link	c.779C>T	p.Ala260Val	missense_variant	Exon 8 of 25	2		ENSP00000438292.1	A8K2U0-2

Frequencies

GnomAD3 genomes

AF:

0.00903

AC:

1373

AN:

152120

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0310

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00432

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000191

Gnomad OTH

AF:

0.00526

GnomAD3 exomes

AF:

0.00223

AC:

555

AN:

249426

Hom.:

AF XY:

0.00173

AC XY:

234

AN XY:

135334

show subpopulations

Gnomad AFR exome

AF:

0.0309

Gnomad AMR exome

AF:

0.00168

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000556

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000106

Gnomad OTH exome

AF:

0.000661

GnomAD4 exome

AF:

0.000950

AC:

1389

AN:

1461812

Hom.:

Cov.:

AF XY:

0.000846

AC XY:

615

AN XY:

727194

show subpopulations

Gnomad4 AFR exome

AF:

0.0317

Gnomad4 AMR exome

AF:

0.00179

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000696

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000890

Gnomad4 OTH exome

AF:

0.00222

GnomAD4 genome

AF:

0.00904

AC:

1376

AN:

152238

Hom.:

Cov.:

AF XY:

0.00880

AC XY:

655

AN XY:

74450

show subpopulations

Gnomad4 AFR

AF:

0.0310

Gnomad4 AMR

AF:

0.00432

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000191

Gnomad4 OTH

AF:

0.00520

Alfa

AF:

0.00128

Hom.:

Bravo

AF:

0.0105

ESP6500AA

AF:

0.0288

AC:

119

ESP6500EA

AF:

0.000119

AC:

ExAC

AF:

0.00272

AC:

329

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000273

EpiControl

AF:

0.000119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Aug 12, 2019

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: A2ML1 c.2252C>T (p.Ala751Val) results in a non-conservative amino acid change located in the Alpha-2-macroglobulin domain of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0022 in 249426 control chromosomes, predominantly at a frequency of 0.031 within the African or African-American subpopulation in the gnomAD database, including 13 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 7750-folds over 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 African or African-American origin. Two ClinVar submissions (evaluation after 2014) cites the variant as benign. Based on the evidence outlined above, the variant was classified as benign. -

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 07, 2022

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 03, 2017

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not provided

Benign:2

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.084

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.69

CADD

Benign

7.1

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0049

T;T;.

Eigen

Benign

-0.81

Eigen_PC

Benign

-0.71

FATHMM_MKL

Benign

0.21

LIST_S2

Benign

0.57

T;T;T

MetaRNN

Benign

0.0038

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.73

N;.;.

PrimateAI

Benign

0.30

PROVEAN

Benign

-1.4

N;N;N

REVEL

Benign

0.096

Sift

Benign

0.082

T;D;D

Sift4G

Uncertain

0.036

D;D;D

Polyphen

0.029

B;.;.

Vest4

0.047

MVP

0.040

MPC

0.11

ClinPred

0.018

GERP RS

3.3

Varity_R

0.023

gMVP

0.22

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