12-9079271-C-T

Position:

chr12-9079271-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_000014.6(A2M):c.3092G>A(p.Arg1031Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000551 in 1,613,642 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.00098 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00051 ( 3 hom. )

Consequence

A2M
NM_000014.6 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:2

Conservation

PhyloP100: -0.735

Variant links:

Genes affected

A2M (HGNC:7): (alpha-2-macroglobulin) The protein encoded by this gene is a protease inhibitor and cytokine transporter. It uses a bait-and-trap mechanism to inhibit a broad spectrum of proteases, including trypsin, thrombin and collagenase. It can also inhibit inflammatory cytokines, and it thus disrupts inflammatory cascades. Mutations in this gene are a cause of alpha-2-macroglobulin deficiency. This gene is implicated in Alzheimer's disease (AD) due to its ability to mediate the clearance and degradation of A-beta, the major component of beta-amyloid deposits. A related pseudogene, which is also located on the p arm of chromosome 12, has been identified. [provided by RefSeq, Nov 2016]

A2M links:

KLRG1 (HGNC:):

KLRG1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.026189327).

BP6

Variant 12-9079271-C-T is Benign according to our data. Variant chr12-9079271-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 711716.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High AC in GnomAd4 at 149 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
A2M	NM_000014.6 linkuse as main transcript	c.3092G>A	p.Arg1031Gln	missense_variant	25/36	ENST00000318602.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
A2M	ENST00000318602.12 linkuse as main transcript	c.3092G>A	p.Arg1031Gln	missense_variant	25/36	1	NM_000014.6	P1
A2M	ENST00000542567.1 linkuse as main transcript	n.447G>A		non_coding_transcript_exon_variant	4/5	4
A2M	ENST00000543436.2 linkuse as main transcript	n.451+10641G>A		intron_variant, non_coding_transcript_variant		5
A2M	ENST00000545828.1 linkuse as main transcript	n.349-6550G>A		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes

AF:

0.000980

AC:

149

AN:

152032

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000967

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00550

Gnomad ASJ

AF:

0.00547

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000485

Gnomad OTH

AF:

0.000956

GnomAD3 exomes

AF:

0.000800

AC:

201

AN:

251156

Hom.:

AF XY:

0.000818

AC XY:

111

AN XY:

135756

show subpopulations

Gnomad AFR exome

AF:

0.0000617

Gnomad AMR exome

AF:

0.00168

Gnomad ASJ exome

AF:

0.00387

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.000752

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000599

Gnomad OTH exome

AF:

0.00163

GnomAD4 exome

AF:

0.000506

AC:

740

AN:

1461492

Hom.:

Cov.:

AF XY:

0.000549

AC XY:

399

AN XY:

727048

show subpopulations

Gnomad4 AFR exome

AF:

0.0000598

Gnomad4 AMR exome

AF:

0.00168

Gnomad4 ASJ exome

AF:

0.00433

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.000893

Gnomad4 FIN exome

AF:

0.0000562

Gnomad4 NFE exome

AF:

0.000339

Gnomad4 OTH exome

AF:

0.000994

GnomAD4 genome

AF:

0.000979

AC:

149

AN:

152150

Hom.:

Cov.:

AF XY:

0.00110

AC XY:

AN XY:

74362

show subpopulations

Gnomad4 AFR

AF:

0.0000964

Gnomad4 AMR

AF:

0.00550

Gnomad4 ASJ

AF:

0.00547

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00104

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000485

Gnomad4 OTH

AF:

0.000946

Alfa

AF:

0.000678

Hom.:

Bravo

AF:

0.00103

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000698

AC:

ExAC

AF:

0.000626

AC:

EpiCase

AF:

0.000873

EpiControl

AF:

0.00107

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

A2M-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 13, 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). -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 10, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.072

BayesDel_addAF

Benign

-0.67

BayesDel_noAF

Benign

-0.75

CADD

Benign

0.32

DANN

Benign

0.68

DEOGEN2

Benign

0.056

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.025

LIST_S2

Benign

0.36

M_CAP

Benign

0.0077

MetaRNN

Benign

0.026

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.28

MutationTaster

Benign

1.0

PrimateAI

Benign

0.24

PROVEAN

Benign

0.34

REVEL

Benign

0.11

Sift

Benign

0.69

Sift4G

Benign

0.30

Polyphen

0.027

Vest4

0.14

MVP

0.51

MPC

0.25

ClinPred

0.0064

GERP RS

-4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.055

gMVP

0.063

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