6-29829643-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001384290.1(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. 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 NM_001384290.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.716

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

Verdict is Benign. Variant got -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HLA-G	NM_001384290.1	c.845C>T	p.Thr282Met	missense_variant	4/7	ENST00000360323.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HLA-G	ENST00000360323.11	c.845C>T	p.Thr282Met	missense_variant	4/7		NM_001384290.1	P2

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

GnomAD3 exomes AF: 0.0566 AC: 14216 AN: 251030 Hom.: 575 AF XY: 0.0623 AC XY: 8452 AN XY: 135714

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 SAS exome AF: 0.134

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

Gnomad4 AFR exome AF: 0.0127

Gnomad4 AMR exome AF: 0.0361

Gnomad4 ASJ exome AF: 0.0989

Gnomad4 EAS exome AF: 0.00753

Gnomad4 SAS exome AF: 0.132

Gnomad4 FIN exome AF: 0.0228

Gnomad4 NFE exome AF: 0.0609

Gnomad4 OTH exome AF: 0.0660

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

Gnomad4 AFR AF: 0.0136

Gnomad4 AMR AF: 0.0422

Gnomad4 ASJ AF: 0.0938

Gnomad4 EAS AF: 0.0150

Gnomad4 SAS AF: 0.124

Gnomad4 FIN AF: 0.0245

Gnomad4 NFE AF: 0.0594

Gnomad4 OTH AF: 0.0564

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 v4.3

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
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.48
FATHMM_MKL	Benign	0.016	N
LIST_S2	Benign	0.34	T;T;.;.
MetaRNN	Benign	0.0070	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	D;N;N;N;N
PrimateAI	Benign	0.24	T
PROVEAN	Uncertain	-3.3	D;D;D;D
REVEL	Benign	0.11
Sift	Uncertain	0.0090	D;D;D;D
Sift4G	Uncertain	0.036	D;D;D;D
Polyphen		1.0	D;D;D;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

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

Publications

LitVar

Other links and lift over

dbSNP: rs12722482; hg19: chr6-29797420;