Variant 12-9077429-A-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_000014.6(A2M):c.3277-9T>G variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00199 in 1,609,894 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

Frequency

Genomes: 𝑓 0.0016 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0020 ( 3 hom. )

Consequence

A2M
NM_000014.6 splice_polypyrimidine_tract, intron

Scores

Splicing: ADA: 0.003897

Clinical Significance

Likely benign no assertion criteria provided B:1

Conservation

PhyloP100: -1.09

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.84).

BP6

Variant 12-9077429-A-C is Benign according to our data. Variant chr12-9077429-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 3057128.Status of the report is no_assertion_criteria_provided, 0 stars.

BS2

High AC in GnomAd4 at 250 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
A2M	NM_000014.6 linkuse as main transcript	c.3277-9T>G		splice_polypyrimidine_tract_variant, intron_variant		ENST00000318602.12

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Appris
A2M	ENST00000318602.12 linkuse as main transcript	c.3277-9T>G	splice_polypyrimidine_tract_variant, intron_variant	1	NM_000014.6	P1
A2M	ENST00000543436.2 linkuse as main transcript	n.452-9617T>G	intron_variant, non_coding_transcript_variant	5
A2M	ENST00000545828.1 linkuse as main transcript	n.349-4708T>G	intron_variant, non_coding_transcript_variant	4

Frequencies

GnomAD3 genomes

AF:

0.00164

AC:

250

AN:

152212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000458

Gnomad AMI

AF:

0.0274

Gnomad AMR

AF:

0.00386

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.000377

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00200

Gnomad OTH

AF:

0.00287

GnomAD3 exomes

AF:

0.00154

AC:

379

AN:

246096

Hom.:

AF XY:

0.00159

AC XY:

212

AN XY:

133042

show subpopulations

Gnomad AFR exome

AF:

0.000386

Gnomad AMR exome

AF:

0.00168

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000202

Gnomad FIN exome

AF:

0.000793

Gnomad NFE exome

AF:

0.00252

Gnomad OTH exome

AF:

0.00216

GnomAD4 exome

AF:

0.00202

AC:

2950

AN:

1457564

Hom.:

Cov.:

AF XY:

0.00197

AC XY:

1426

AN XY:

724994

show subpopulations

Gnomad4 AFR exome

AF:

0.000359

Gnomad4 AMR exome

AF:

0.00189

Gnomad4 ASJ exome

AF:

0.0000384

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000140

Gnomad4 FIN exome

AF:

0.00105

Gnomad4 NFE exome

AF:

0.00243

Gnomad4 OTH exome

AF:

0.00144

GnomAD4 genome

AF:

0.00164

AC:

250

AN:

152330

Hom.:

Cov.:

AF XY:

0.00140

AC XY:

104

AN XY:

74486

show subpopulations

Gnomad4 AFR

AF:

0.000457

Gnomad4 AMR

AF:

0.00386

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.000377

Gnomad4 NFE

AF:

0.00200

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.00172

Hom.:

Bravo

AF:

0.00209

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

A2M-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 25, 2023

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). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

3.0

DANN

Benign

0.53

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0039

dbscSNV1_RF

Benign

0.066

SpliceAI score (max)

0.040

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