chr12-9079672-T-C

Variant names:

• chr12-9079672-T-C
• rs669
• NM_000014.6:c.2998A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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. 15/21 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.907
• Publications: 114 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 -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 VariationId is 18171.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.351 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.2998A>G	p.Ile1000Val	missense	Exon 24 of 36	NP_000005.3	P01023
	A2M	NM_001347423.2		c.2998A>G	p.Ile1000Val	missense	Exon 25 of 37	NP_001334352.2	P01023
	A2M	NM_001347424.2		c.2698A>G	p.Ile900Val	missense	Exon 24 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.2998A>G	p.Ile1000Val	missense	Exon 24 of 36	ENSP00000323929.8	P01023
	A2M	ENST00000891833.1		c.3136A>G	p.Ile1046Val	missense	Exon 25 of 37	ENSP00000561892.1
	A2M	ENST00000956132.1		c.2998A>G	p.Ile1000Val	missense	Exon 24 of 36	ENSP00000626191.1

Frequencies

GnomAD3 genomes AF: 0.323 AC: 49127 AN: 151996 Hom.: 8331 Cov.: 32

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

GnomAD2 exomes AF: 0.310 AC: 77045 AN: 248678 AF XY: 0.303

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 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.: 35 AF XY: 0.324 AC XY: 235261 AN XY: 726318

African (AFR) AF: 0.295 AC: 9868 AN: 33434

American (AMR) AF: 0.383 AC: 17094 AN: 44586

Ashkenazi Jewish (ASJ) AF: 0.235 AC: 6137 AN: 26118

East Asian (EAS) AF: 0.0754 AC: 2993 AN: 39680

South Asian (SAS) AF: 0.203 AC: 17515 AN: 86186

European-Finnish (FIN) AF: 0.406 AC: 21649 AN: 53366

Middle Eastern (MID) AF: 0.244 AC: 1402 AN: 5756

European-Non Finnish (NFE) AF: 0.347 AC: 384806 AN: 1110492

Other (OTH) AF: 0.307 AC: 18510 AN: 60318

GnomAD4 genome AF: 0.323 AC: 49174 AN: 152114 Hom.: 8339 Cov.: 32 AF XY: 0.324 AC XY: 24077 AN XY: 74362

African (AFR) AF: 0.303 AC: 12591 AN: 41506

American (AMR) AF: 0.359 AC: 5486 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.245 AC: 848 AN: 3468

East Asian (EAS) AF: 0.0811 AC: 420 AN: 5180

South Asian (SAS) AF: 0.188 AC: 906 AN: 4824

European-Finnish (FIN) AF: 0.418 AC: 4413 AN: 10564

Middle Eastern (MID) AF: 0.231 AC: 68 AN: 294

European-Non Finnish (NFE) AF: 0.347 AC: 23559 AN: 67968

Other (OTH) AF: 0.299 AC: 633 AN: 2114

Alfa AF: 0.327 Hom.: 38421

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	ALPHA-2-MACROGLOBULIN POLYMORPHISM (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.74	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	12
DANN	Benign	0.74
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.95
Eigen_PC	Benign	-0.94
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.77	T
MetaRNN	Benign	0.0036	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.1	L
PhyloP100		0.91
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.89	N
REVEL	Benign	0.038
Sift	Benign	0.15	T
Sift4G	Benign	0.28	T
Polyphen		0.019	B
Vest4		0.072
MPC		0.18
ClinPred		0.0021	T
GERP RS		0.089
Varity_R		0.074
gMVP		0.12
Mutation Taster		=97/3	polymorphism (auto)

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

Other links and lift over

dbSNP: rs669; hg19: chr12-9232268; COSMIC: COSV59386644; COSMIC: COSV59386644;