rs669

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000014.6(A2M):c.2998A>G(p.Ile1000Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.328 in 1,612,050 control chromosomes in the GnomAD database, including 90,577 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.32 ( 8339 hom., cov: 32)

Exomes 𝑓: 0.33 ( 82238 hom. )

Consequence

A2M
NM_000014.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.907

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:6380): (killer cell lectin like receptor G1) Natural killer (NK) cells are lymphocytes that can mediate lysis of certain tumor cells and virus-infected cells without previous activation. They can also regulate specific humoral and cell-mediated immunity. The protein encoded by this gene belongs to the killer cell lectin-like receptor (KLR) family, which is a group of transmembrane proteins preferentially expressed in NK cells. Studies in mice suggested that the expression of this gene may be regulated by MHC class I molecules. [provided by RefSeq, Jun 2016]

KLRG1 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=0.0035947263).

BP6

Variant 12-9079672-T-C is Benign according to our data. Variant chr12-9079672-T-C is described in ClinVar as [Benign]. Clinvar id is 18171.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-9079672-T-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.351 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
A2M	NM_000014.6 link	c.2998A>G	p.Ile1000Val	missense_variant	Exon 24 of 36	ENST00000318602.12	NP_000005.3	P01023

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
A2M	ENST00000318602.12 link	c.2998A>G	p.Ile1000Val	missense_variant	Exon 24 of 36	1	NM_000014.6	ENSP00000323929.8	P01023
A2M	ENST00000542567.1 link	n.353A>G		non_coding_transcript_exon_variant	Exon 3 of 5	4
A2M	ENST00000543436.2 link	n.451+10240A>G		intron_variant	Intron 3 of 3	5
A2M	ENST00000545828.1 link	n.349-6951A>G		intron_variant	Intron 3 of 4	4

Frequencies

GnomAD3 genomes

AF:

0.323

AC:

49127

AN:

151996

Hom.:

8331

Cov.:

show subpopulations

Gnomad AFR

AF:

0.303

Gnomad AMI

AF:

0.275

Gnomad AMR

AF:

0.359

Gnomad ASJ

AF:

0.245

Gnomad EAS

AF:

0.0809

Gnomad SAS

AF:

0.186

Gnomad FIN

AF:

0.418

Gnomad MID

AF:

0.228

Gnomad NFE

AF:

0.347

Gnomad OTH

AF:

0.300

GnomAD3 exomes

AF:

0.310

AC:

77045

AN:

248678

Hom.:

13020

AF XY:

0.303

AC XY:

40840

AN XY:

134838

show subpopulations

Gnomad AFR exome

AF:

0.307

Gnomad AMR exome

AF:

0.386

Gnomad ASJ exome

AF:

0.236

Gnomad EAS exome

AF:

0.0878

Gnomad SAS exome

AF:

0.199

Gnomad FIN exome

AF:

0.405

Gnomad NFE exome

AF:

0.341

Gnomad OTH exome

AF:

0.308

GnomAD4 exome

AF:

0.329

AC:

479974

AN:

1459936

Hom.:

82238

Cov.:

AF XY:

0.324

AC XY:

235261

AN XY:

726318

show subpopulations

Gnomad4 AFR exome

AF:

0.295

Gnomad4 AMR exome

AF:

0.383

Gnomad4 ASJ exome

AF:

0.235

Gnomad4 EAS exome

AF:

0.0754

Gnomad4 SAS exome

AF:

0.203

Gnomad4 FIN exome

AF:

0.406

Gnomad4 NFE exome

AF:

0.347

Gnomad4 OTH exome

AF:

0.307

GnomAD4 genome

AF:

0.323

AC:

49174

AN:

152114

Hom.:

8339

Cov.:

AF XY:

0.324

AC XY:

24077

AN XY:

74362

show subpopulations

Gnomad4 AFR

AF:

0.303

Gnomad4 AMR

AF:

0.359

Gnomad4 ASJ

AF:

0.245

Gnomad4 EAS

AF:

0.0811

Gnomad4 SAS

AF:

0.188

Gnomad4 FIN

AF:

0.418

Gnomad4 NFE

AF:

0.347

Gnomad4 OTH

AF:

0.299

Alfa

AF:

0.326

Hom.:

20401

Bravo

AF:

0.318

TwinsUK

AF:

0.337

AC:

1251

ALSPAC

AF:

0.345

AC:

1329

ESP6500AA

AF:

0.302

AC:

1235

ESP6500EA

AF:

0.328

AC:

2776

ExAC

AF:

0.308

AC:

37285

Asia WGS

AF:

0.172

AC:

600

AN:

3478

EpiCase

AF:

0.330

EpiControl

AF:

0.316

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 17, 2019	This variant is associated with the following publications: (PMID: 9811940, 24039871) -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

ALPHA-2-MACROGLOBULIN POLYMORPHISM

Benign:1

Benign, no assertion criteria provided

literature only

OMIM

Mar 01, 2004

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.74

BayesDel_noAF

Benign

-0.70

CADD

Benign

DANN

Benign

0.74

DEOGEN2

Benign

0.14

Eigen

Benign

-0.95

Eigen_PC

Benign

-0.94

FATHMM_MKL

Benign

0.20

LIST_S2

Benign

0.77

MetaRNN

Benign

0.0036

MetaSVM

Benign

-0.94

MutationAssessor

Benign

1.1

PrimateAI

Benign

0.31

PROVEAN

Benign

-0.89

REVEL

Benign

0.038

Sift

Benign

0.15

Sift4G

Benign

0.28

Polyphen

0.019

Vest4

0.072

MPC

0.18

ClinPred

0.0021

GERP RS

0.089

Varity_R

0.074

gMVP

0.12

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