chr12-9115877-A-C

Variant names:

• chr12-9115877-A-C
• rs226380
• NM_000014.6:c.-28T>G

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• 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
• Publications: 33 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.017).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.757 is higher than 0.05.

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.-28T>G		5_prime_UTR	Exon 1 of 36	NP_000005.3	P01023
	A2M	NM_001347424.2		c.-481T>G		5_prime_UTR	Exon 1 of 36	NP_001334353.2
	A2M	NM_001347425.2		c.-318T>G		5_prime_UTR	Exon 1 of 35	NP_001334354.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	A2M	ENST00000318602.12	TSL:1 MANE Select	c.-28T>G		5_prime_UTR	Exon 1 of 36	ENSP00000323929.8	P01023
	A2M	ENST00000891833.1		c.-28T>G		5_prime_UTR	Exon 1 of 37	ENSP00000561892.1
	A2M	ENST00000956132.1		c.-28T>G		5_prime_UTR	Exon 1 of 36	ENSP00000626191.1

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

GnomAD2 exomes AF: 0.468 AC: 116460 AN: 248898 AF XY: 0.461

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 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

African (AFR) AF: 0.769 AC: 25256 AN: 32846

American (AMR) AF: 0.481 AC: 21459 AN: 44604

Ashkenazi Jewish (ASJ) AF: 0.430 AC: 11136 AN: 25896

East Asian (EAS) AF: 0.114 AC: 4505 AN: 39422

South Asian (SAS) AF: 0.368 AC: 31464 AN: 85576

European-Finnish (FIN) AF: 0.513 AC: 27351 AN: 53272

Middle Eastern (MID) AF: 0.433 AC: 2457 AN: 5670

European-Non Finnish (NFE) AF: 0.503 AC: 545877 AN: 1085356

Other (OTH) AF: 0.479 AC: 28372 AN: 59278

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

African (AFR) AF: 0.764 AC: 31637 AN: 41412

American (AMR) AF: 0.516 AC: 7869 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.454 AC: 1574 AN: 3470

East Asian (EAS) AF: 0.117 AC: 606 AN: 5164

South Asian (SAS) AF: 0.353 AC: 1698 AN: 4812

European-Finnish (FIN) AF: 0.518 AC: 5455 AN: 10536

Middle Eastern (MID) AF: 0.459 AC: 134 AN: 292

European-Non Finnish (NFE) AF: 0.511 AC: 34674 AN: 67900

Other (OTH) AF: 0.504 AC: 1064 AN: 2110

Alfa AF: 0.512 Hom.: 33769

Bravo AF: 0.568

Asia WGS AF: 0.311 AC: 1084 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	9.6
DANN	Benign	0.75
PhyloP100		-0.26
PromoterAI		-0.12	Neutral
Mutation Taster		=300/0	polymorphism (auto)

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

Other links and lift over

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