6-29828148-C-T

Variant names:

• chr6-29828148-C-T
• rs747667406
• NM_001384290.1:c.175C>T
• HLA-G p.Arg59Trp

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001384290.1(HLA-G):​c.175C>T​(p.Arg59Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,626 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. R59R) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: HLA-G NM_001384290.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.24
• Publications: 0 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]

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

HLA-F-AS1 (HGNC:26645): (HLA-F antisense RNA 1)

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001384290.1. 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
	HLA-G	NM_001384290.1	MANE Select	c.175C>T	p.Arg59Trp	missense	Exon 2 of 7	NP_001371219.1	Q6DU14
	HLA-G	NM_001363567.2		c.190C>T	p.Arg64Trp	missense	Exon 3 of 8	NP_001350496.1	Q5RJ85
	HLA-G	NM_001384280.1		c.190C>T	p.Arg64Trp	missense	Exon 4 of 9	NP_001371209.1	Q5RJ85

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HLA-G	ENST00000360323.11	TSL:6 MANE Select	c.175C>T	p.Arg59Trp	missense	Exon 2 of 7	ENSP00000353472.6	P17693-1
	HLA-G	ENST00000376828.6	TSL:6	c.190C>T	p.Arg64Trp	missense	Exon 3 of 8	ENSP00000366024.2	Q5RJ85
	HLA-G	ENST00000936944.1		c.175C>T	p.Arg59Trp	missense	Exon 2 of 7	ENSP00000607003.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460626 Hom.: 0 Cov.: 90 AF XY: 0.00 AC XY: 0 AN XY: 726686

African (AFR) AF: 0.00 AC: 0 AN: 33446

American (AMR) AF: 0.00 AC: 0 AN: 44646

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26068

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.00 AC: 0 AN: 86234

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52774

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5744

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111682

Other (OTH) AF: 0.00 AC: 0 AN: 60348

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.055	T
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.53
FATHMM_MKL	Benign	0.045	N
LIST_S2	Benign	0.54	T
M_CAP	Benign	0.0058	T
MetaRNN	Uncertain	0.44	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Pathogenic	3.3	M
PhyloP100		-1.2
PrimateAI	Uncertain	0.61	T
PROVEAN	Pathogenic	-6.5	D
REVEL	Benign	0.065
Sift	Uncertain	0.010	D
Sift4G	Uncertain	0.012	D
PromoterAI		0.0084	Neutral
Varity_R		0.51
gMVP		0.47
Mutation Taster		=77/23	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs747667406;

hg19: chr6-29795925;