chr12-8861187-C-T

Position:

chr12-8861187-C-T

Variant summary

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

The NM_144670.6(A2ML1):c.3392C>T(p.Thr1131Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00342 in 1,614,122 control chromosomes in the GnomAD database, including 89 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 Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.012 ( 43 hom., cov: 32)

Exomes 𝑓: 0.0025 ( 46 hom. )

Consequence

A2ML1
NM_144670.6 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.0820

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0026110709).

BP6

Variant 12-8861187-C-T is Benign according to our data. Variant chr12-8861187-C-T is described in ClinVar as [Benign]. Clinvar id is 241905.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-8861187-C-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0125 (1896/152242) while in subpopulation AFR AF= 0.0407 (1688/41508). AF 95% confidence interval is 0.0391. There are 43 homozygotes in gnomad4. There are 917 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 1896 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
A2ML1	NM_144670.6 linkuse as main transcript	c.3392C>T	p.Thr1131Met	missense_variant	28/36	ENST00000299698.12	NP_653271.3	B3KVV6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
A2ML1	ENST00000299698.12 linkuse as main transcript	c.3392C>T	p.Thr1131Met	missense_variant	28/36	1	NM_144670.6	ENSP00000299698.7	A8K2U0-1
A2ML1	ENST00000541459.5 linkuse as main transcript	c.2042C>T	p.Thr681Met	missense_variant	17/25	2		ENSP00000443174.1	H0YGG5
A2ML1	ENST00000539547.5 linkuse as main transcript	c.1919C>T	p.Thr640Met	missense_variant	17/25	2		ENSP00000438292.1	A8K2U0-2
ENSG00000282022	ENST00000631830.1 linkuse as main transcript	n.322-2911G>A		intron_variant		3

Frequencies

GnomAD3 genomes

AF:

0.0124

AC:

1891

AN:

152124

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0407

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00563

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00148

Gnomad OTH

AF:

0.00957

GnomAD3 exomes

AF:

0.00367

AC:

917

AN:

249544

Hom.:

AF XY:

0.00293

AC XY:

396

AN XY:

135382

show subpopulations

Gnomad AFR exome

AF:

0.0436

Gnomad AMR exome

AF:

0.00206

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000980

Gnomad FIN exome

AF:

0.000371

Gnomad NFE exome

AF:

0.00135

Gnomad OTH exome

AF:

0.00115

GnomAD4 exome

AF:

0.00248

AC:

3622

AN:

1461880

Hom.:

Cov.:

AF XY:

0.00223

AC XY:

1621

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.0435

Gnomad4 AMR exome

AF:

0.00253

Gnomad4 ASJ exome

AF:

0.000230

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000696

Gnomad4 FIN exome

AF:

0.000487

Gnomad4 NFE exome

AF:

0.00157

Gnomad4 OTH exome

AF:

0.00434

GnomAD4 genome

AF:

0.0125

AC:

1896

AN:

152242

Hom.:

Cov.:

AF XY:

0.0123

AC XY:

917

AN XY:

74454

show subpopulations

Gnomad4 AFR

AF:

0.0407

Gnomad4 AMR

AF:

0.00562

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000942

Gnomad4 NFE

AF:

0.00148

Gnomad4 OTH

AF:

0.00947

Alfa

AF:

0.00331

Hom.:

Bravo

AF:

0.0141

TwinsUK

AF:

0.00243

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.0371

AC:

146

ESP6500EA

AF:

0.00132

AC:

ExAC

AF:

0.00458

AC:

553

Asia WGS

AF:

0.00202

AC:

AN:

3478

EpiCase

AF:

0.00115

EpiControl

AF:

0.00124

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 30, 2019	Variant summary: A2ML1 c.3392C>T (p.Thr1131Met) results in a non-conservative amino acid change located in the Alpha-macroglobulin like TET domain (IPRO11626) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0037 in 249544 control chromosomes in the gnomAD database, including 16 homozygotes. The observed variant frequency is approximately 919 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 benign. To our knowledge, no occurrence of c.3392C>T in individuals affected with Noonan Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign. Based on the evidence outlined above, the variant was classified as benign. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 15, 2017	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, 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+	-	- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.093

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.54

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.0035

T;T;.

Eigen

Benign

-0.24

Eigen_PC

Benign

-0.45

FATHMM_MKL

Benign

0.13

LIST_S2

Benign

0.81

T;T;T

MetaRNN

Benign

0.0026

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.7

L;.;.

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.33

PROVEAN

Benign

-1.7

N;N;N

REVEL

Benign

0.044

Sift

Uncertain

0.021

D;T;T

Sift4G

Benign

0.065

T;T;T

Polyphen

1.0

D;.;.

Vest4

0.15

MVP

0.15

MPC

0.19

ClinPred

0.010

GERP RS

1.7

Varity_R

0.094

gMVP

0.095

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