rs226380

Positions:

• chr12-9115877-A-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_000014.6(A2M):​c.-28T>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.494 in 1,583,780 control chromosomes in the GnomAD database, including 201,272 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in Lovd as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.56 (25472 hom., cov: 30)
  • Exomes 𝑓: 0.49 (175800 hom.)
• Consequence: A2M NM_000014.6 5_prime_UTR
• Scores: Splicing: ADA: 0.0001008
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.257

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:):

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 12-9115877-A-C is Benign according to our data. Variant chr12-9115877-A-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.757 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
A2M	NM_000014.6	c.-28T>G		5_prime_UTR_variant	1/36	ENST00000318602.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
A2M	ENST00000318602.12	c.-28T>G		5_prime_UTR_variant	1/36	1	NM_000014.6	P1

Frequencies

GnomAD3 genomes AF: 0.560 AC: 85002 AN: 151740 Hom.: 25413 Cov.: 30

Gnomad AFR AF: 0.764

Gnomad AMI AF: 0.454

Gnomad AMR AF: 0.516

Gnomad ASJ AF: 0.454

Gnomad EAS AF: 0.117

Gnomad SAS AF: 0.349

Gnomad FIN AF: 0.518

Gnomad MID AF: 0.458

Gnomad NFE AF: 0.511

Gnomad OTH AF: 0.508

GnomAD3 exomes AF: 0.468 AC: 116460 AN: 248898 Hom.: 29436 AF XY: 0.461 AC XY: 62214 AN XY: 135006

Gnomad AFR exome AF: 0.765

Gnomad AMR exome AF: 0.477

Gnomad ASJ exome AF: 0.427

Gnomad EAS exome AF: 0.122

Gnomad SAS exome AF: 0.363

Gnomad FIN exome AF: 0.513

Gnomad NFE exome AF: 0.503

Gnomad OTH exome AF: 0.466

GnomAD4 exome AF: 0.487 AC: 697877 AN: 1431920 Hom.: 175800 Cov.: 25 AF XY: 0.482 AC XY: 344571 AN XY: 714228

Gnomad4 AFR exome AF: 0.769

Gnomad4 AMR exome AF: 0.481

Gnomad4 ASJ exome AF: 0.430

Gnomad4 EAS exome AF: 0.114

Gnomad4 SAS exome AF: 0.368

Gnomad4 FIN exome AF: 0.513

Gnomad4 NFE exome AF: 0.503

Gnomad4 OTH exome AF: 0.479

GnomAD4 genome AF: 0.561 AC: 85123 AN: 151860 Hom.: 25472 Cov.: 30 AF XY: 0.555 AC XY: 41150 AN XY: 74190

Gnomad4 AFR AF: 0.764

Gnomad4 AMR AF: 0.516

Gnomad4 ASJ AF: 0.454

Gnomad4 EAS AF: 0.117

Gnomad4 SAS AF: 0.353

Gnomad4 FIN AF: 0.518

Gnomad4 NFE AF: 0.511

Gnomad4 OTH AF: 0.504

Alfa AF: 0.504 Hom.: 25638

Bravo AF: 0.568

Asia WGS AF: 0.311 AC: 1084 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	9.6
DANN	Benign	0.75

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00010
dbscSNV1_RF	Benign	0.0
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

Other links and lift over

dbSNP: rs226380; hg19: chr12-9268473; COSMIC: COSV59394574; COSMIC: COSV59394574;