rs72558173

chr6-29828137-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001384290.1(HLA-G):c.164C>T(p.Thr55Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000179 in 1,613,264 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.0010 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000091 (0 hom.)
• Consequence: HLA-G NM_001384290.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.991

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]

HCG4P8 (HGNC:22927): (HLA complex group 4 pseudogene 8)

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.010911822).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HLA-G	NM_001384290.1	c.164C>T	p.Thr55Met	missense_variant	2/7	ENST00000360323.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HLA-G	ENST00000360323.11	c.164C>T	p.Thr55Met	missense_variant	2/7		NM_001384290.1	P2
HCG4P8	ENST00000443049.1	n.228G>A		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes AF: 0.00102 AC: 156 AN: 152232 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00352

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000255 AC: 63 AN: 247116 Hom.: 0 AF XY: 0.000178 AC XY: 24 AN XY: 134522

Gnomad AFR exome AF: 0.00351

Gnomad AMR exome AF: 0.000261

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000910 AC: 133 AN: 1460914 Hom.: 0 Cov.: 89 AF XY: 0.0000770 AC XY: 56 AN XY: 726814

Gnomad4 AFR exome AF: 0.00314

Gnomad4 AMR exome AF: 0.000201

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.000298

GnomAD4 genome AF: 0.00102 AC: 156 AN: 152350 Hom.: 0 Cov.: 34 AF XY: 0.000953 AC XY: 71 AN XY: 74500

Gnomad4 AFR AF: 0.00351

Gnomad4 AMR AF: 0.000588

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000336 Hom.: 0

Bravo AF: 0.00124

ESP6500AA AF: 0.00464 AC: 14

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000298 AC: 36

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.55
Cadd	Benign	20
Dann	Uncertain	1.0
Eigen	Benign	-0.052
Eigen_PC	Benign	-0.34
FATHMM_MKL	Benign	0.016	N
LIST_S2	Benign	0.49	T;T;.;.;T
M_CAP	Benign	0.0016	T
MetaRNN	Benign	0.011	T;T;T;T;T
MetaSVM	Benign	-0.99	T
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-4.6	D;D;D;D;D
REVEL	Benign	0.061
Sift	Pathogenic	0.0	D;D;D;T;D
Sift4G	Uncertain	0.0080	D;D;D;D;D
Polyphen		1.0	D;D;D;D;.
Vest4		0.24
MVP		0.29
MPC		0.86
ClinPred		0.16	T
GERP RS		-0.78
Varity_R		0.081
gMVP		0.40

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs72558173; hg19: chr6-29795914;