chr6-29829643-C-T

Variant names:

• chr6-29829643-C-T
• rs12722482
• NM_001384290.1:c.845C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000360323.11(HLA-G):​c.845C>T​(p.Thr282Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0598 in 1,613,874 control chromosomes in the GnomAD database, including 3,630 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. T282T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.044 (217 hom., cov: 30)
  • Exomes 𝑓: 0.061 (3413 hom.)
• Consequence: HLA-G ENST00000360323.11 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.716
• Publications: 24 publications found

Genes affected

HLA-G (HGNC:4964): (major histocompatibility complex, class I, G) HLA-G belongs to the HLA class I heavy chain paralogues. This class I molecule is a heterodimer consisting of a heavy chain and a light chain (beta-2 microglobulin). The heavy chain is anchored in the membrane. HLA-G is expressed on fetal derived placental cells. The heavy chain is approximately 45 kDa and its gene contains 8 exons. Exon one encodes the leader peptide, exons 2 and 3 encode the alpha1 and alpha2 domain, which both bind the peptide, exon 4 encodes the alpha3 domain, exon 5 encodes the transmembrane region, and exon 6 encodes the cytoplasmic tail. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0069839656).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.116 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000360323.11. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HLA-G	NM_001384290.1	MANE Select	c.845C>T	p.Thr282Met	missense	Exon 4 of 7	NP_001371219.1
	HLA-G	NM_001363567.2		c.860C>T	p.Thr287Met	missense	Exon 5 of 8	NP_001350496.1
	HLA-G	NM_001384280.1		c.860C>T	p.Thr287Met	missense	Exon 6 of 9	NP_001371209.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HLA-G	ENST00000360323.11	TSL:6 MANE Select	c.845C>T	p.Thr282Met	missense	Exon 4 of 7	ENSP00000353472.6
	HLA-G	ENST00000376828.6	TSL:6	c.860C>T	p.Thr287Met	missense	Exon 5 of 8	ENSP00000366024.2
	HLA-G	ENST00000376818.7	TSL:6	c.569C>T	p.Thr190Met	missense	Exon 3 of 6	ENSP00000366014.3

Frequencies

GnomAD3 genomes AF: 0.0440 AC: 6683 AN: 151940 Hom.: 217 Cov.: 30

Gnomad AFR AF: 0.0137

Gnomad AMI AF: 0.0230

Gnomad AMR AF: 0.0423

Gnomad ASJ AF: 0.0938

Gnomad EAS AF: 0.0149

Gnomad SAS AF: 0.124

Gnomad FIN AF: 0.0245

Gnomad MID AF: 0.111

Gnomad NFE AF: 0.0594

Gnomad OTH AF: 0.0565

GnomAD2 exomes AF: 0.0566 AC: 14216 AN: 251030 AF XY: 0.0623

Gnomad AFR exome AF: 0.0114

Gnomad AMR exome AF: 0.0358

Gnomad ASJ exome AF: 0.0995

Gnomad EAS exome AF: 0.00870

Gnomad FIN exome AF: 0.0206

Gnomad NFE exome AF: 0.0590

Gnomad OTH exome AF: 0.0669

GnomAD4 exome AF: 0.0615 AC: 89856 AN: 1461816 Hom.: 3413 Cov.: 36 AF XY: 0.0642 AC XY: 46667 AN XY: 727210

African (AFR) AF: 0.0127 AC: 425 AN: 33480

American (AMR) AF: 0.0361 AC: 1613 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0989 AC: 2586 AN: 26136

East Asian (EAS) AF: 0.00753 AC: 299 AN: 39700

South Asian (SAS) AF: 0.132 AC: 11407 AN: 86252

European-Finnish (FIN) AF: 0.0228 AC: 1219 AN: 53418

Middle Eastern (MID) AF: 0.114 AC: 655 AN: 5766

European-Non Finnish (NFE) AF: 0.0609 AC: 67664 AN: 1111946

Other (OTH) AF: 0.0660 AC: 3988 AN: 60394

GnomAD4 genome AF: 0.0439 AC: 6676 AN: 152058 Hom.: 217 Cov.: 30 AF XY: 0.0447 AC XY: 3319 AN XY: 74302

African (AFR) AF: 0.0136 AC: 565 AN: 41496

American (AMR) AF: 0.0422 AC: 645 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.0938 AC: 325 AN: 3466

East Asian (EAS) AF: 0.0150 AC: 77 AN: 5144

South Asian (SAS) AF: 0.124 AC: 596 AN: 4812

European-Finnish (FIN) AF: 0.0245 AC: 259 AN: 10580

Middle Eastern (MID) AF: 0.105 AC: 31 AN: 294

European-Non Finnish (NFE) AF: 0.0594 AC: 4038 AN: 67968

Other (OTH) AF: 0.0564 AC: 119 AN: 2110

Alfa AF: 0.0553 Hom.: 131

Bravo AF: 0.0425

TwinsUK AF: 0.0515 AC: 191

ALSPAC AF: 0.0560 AC: 216

ESP6500AA AF: 0.0148 AC: 65

ESP6500EA AF: 0.0633 AC: 544

ExAC AF: 0.0572 AC: 6942

Asia WGS AF: 0.0580 AC: 205 AN: 3478

EpiCase AF: 0.0674

EpiControl AF: 0.0659

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.059	T
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.48
FATHMM_MKL	Benign	0.016	N
LIST_S2	Benign	0.34	T
MetaRNN	Benign	0.0070	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Pathogenic	3.5	M
PhyloP100		-0.72
PrimateAI	Benign	0.24	T
PROVEAN	Uncertain	-3.3	D
REVEL	Benign	0.11
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.036	D
Polyphen		1.0	D
Vest4		0.074
MPC		1.4
ClinPred		0.052	T
GERP RS		0.31
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.067
gMVP		0.35
Mutation Taster		=92/8	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: rs12722482; hg19: chr6-29797420; COSMIC: COSV107469007; COSMIC: COSV107469007;