rs372050343

Variant names:

• chr12-9076832-A-G
• rs372050343
• NM_000014.6:c.3456T>C

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Strong BP6_Moderate BP7

The NM_000014.6(A2M):​c.3456T>C​(p.Tyr1152Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00026 in 1,614,060 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0014 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00014 (0 hom.)
• Consequence: A2M NM_000014.6 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.210
• Publications: 1 publications found

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]

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]

ACMG classification

Our verdict: Benign. The variant received -7 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BP6: Variant 12-9076832-A-G is Benign according to our data. Variant chr12-9076832-A-G is described in ClinVar as Benign. ClinVar VariationId is 781242.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.21 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000014.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	A2M	NM_000014.6	MANE Select	c.3456T>C	p.Tyr1152Tyr	synonymous	Exon 28 of 36	NP_000005.3	P01023
	A2M	NM_001347423.2		c.3456T>C	p.Tyr1152Tyr	synonymous	Exon 29 of 37	NP_001334352.2	P01023
	A2M	NM_001347424.2		c.3156T>C	p.Tyr1052Tyr	synonymous	Exon 28 of 36	NP_001334353.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	A2M	ENST00000318602.12	TSL:1 MANE Select	c.3456T>C	p.Tyr1152Tyr	synonymous	Exon 28 of 36	ENSP00000323929.8	P01023
	A2M	ENST00000891833.1		c.3594T>C	p.Tyr1198Tyr	synonymous	Exon 29 of 37	ENSP00000561892.1
	A2M	ENST00000956132.1		c.3456T>C	p.Tyr1152Tyr	synonymous	Exon 28 of 36	ENSP00000626191.1

Frequencies

GnomAD3 genomes AF: 0.00142 AC: 216 AN: 152166 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000852

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: 0.00

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.000392 AC: 98 AN: 249840 AF XY: 0.000318

Gnomad AFR exome AF: 0.00554

Gnomad AMR exome AF: 0.000261

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000329

GnomAD4 exome AF: 0.000139 AC: 203 AN: 1461776 Hom.: 0 Cov.: 31 AF XY: 0.000116 AC XY: 84 AN XY: 727190

African (AFR) AF: 0.00490 AC: 164 AN: 33478

American (AMR) AF: 0.000313 AC: 14 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86242

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5726

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111970

Other (OTH) AF: 0.000364 AC: 22 AN: 60384

GnomAD4 genome AF: 0.00142 AC: 216 AN: 152284 Hom.: 1 Cov.: 32 AF XY: 0.00146 AC XY: 109 AN XY: 74470

African (AFR) AF: 0.00481 AC: 200 AN: 41566

American (AMR) AF: 0.000850 AC: 13 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68020

Other (OTH) AF: 0.00142 AC: 3 AN: 2116

Alfa AF: 0.000850 Hom.: 0

Bravo AF: 0.00165

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	4.9
DANN	Benign	0.47
PhyloP100		-0.21
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs372050343; hg19: chr12-9229428; COSMIC: COSV59387215; COSMIC: COSV59387215;