rs35674592

Variant names:

• chr6-29827179-G-T
• rs35674592
• NM_001363567.2:c.6+135G>T

Variant summary

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

The NM_001363567.2(HLA-G):​c.6+135G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.498 in 454,828 control chromosomes in the GnomAD database, including 58,557 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.

• Frequency:
  • Genomes: 𝑓 0.49 (18145 hom., cov: 32)
  • Exomes 𝑓: 0.50 (40412 hom.)
• Consequence: HLA-G NM_001363567.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0950
• Publications: 8 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]

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

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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.647 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HLA-G	NM_001363567.2	c.6+135G>T		intron_variant	Intron 1 of 7		NP_001350496.1
HLA-G	NM_001384280.1	c.6+135G>T		intron_variant	Intron 2 of 8		NP_001371209.1
HLA-G	NM_002127.6	c.-113+135G>T		intron_variant	Intron 1 of 7		NP_002118.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HLA-G	ENST00000376828.6	c.6+135G>T		intron_variant	Intron 1 of 7	6		ENSP00000366024.2
HLA-G	ENST00000428701.6	n.66+135G>T		intron_variant	Intron 1 of 4	6
HLA-F-AS1	ENST00000849927.1	n.26+1292C>A		intron_variant	Intron 1 of 3

Frequencies

GnomAD3 genomes AF: 0.486 AC: 73733 AN: 151850 Hom.: 18122 Cov.: 32

Gnomad AFR AF: 0.511

Gnomad AMI AF: 0.463

Gnomad AMR AF: 0.515

Gnomad ASJ AF: 0.567

Gnomad EAS AF: 0.612

Gnomad SAS AF: 0.666

Gnomad FIN AF: 0.342

Gnomad MID AF: 0.589

Gnomad NFE AF: 0.459

Gnomad OTH AF: 0.500

GnomAD4 exome AF: 0.505 AC: 152852 AN: 302860 Hom.: 40412 AF XY: 0.525 AC XY: 89945 AN XY: 171482

African (AFR) AF: 0.511 AC: 4138 AN: 8102

American (AMR) AF: 0.501 AC: 12990 AN: 25908

Ashkenazi Jewish (ASJ) AF: 0.569 AC: 5689 AN: 9994

East Asian (EAS) AF: 0.606 AC: 5537 AN: 9138

South Asian (SAS) AF: 0.670 AC: 38901 AN: 58098

European-Finnish (FIN) AF: 0.339 AC: 7689 AN: 22690

Middle Eastern (MID) AF: 0.539 AC: 1206 AN: 2238

European-Non Finnish (NFE) AF: 0.457 AC: 69842 AN: 152962

Other (OTH) AF: 0.500 AC: 6860 AN: 13730

GnomAD4 genome AF: 0.486 AC: 73797 AN: 151968 Hom.: 18145 Cov.: 32 AF XY: 0.486 AC XY: 36078 AN XY: 74264

African (AFR) AF: 0.511 AC: 21139 AN: 41398

American (AMR) AF: 0.515 AC: 7863 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.567 AC: 1969 AN: 3470

East Asian (EAS) AF: 0.611 AC: 3165 AN: 5176

South Asian (SAS) AF: 0.667 AC: 3218 AN: 4828

European-Finnish (FIN) AF: 0.342 AC: 3603 AN: 10544

Middle Eastern (MID) AF: 0.582 AC: 171 AN: 294

European-Non Finnish (NFE) AF: 0.459 AC: 31181 AN: 67958

Other (OTH) AF: 0.506 AC: 1066 AN: 2106

Alfa AF: 0.471 Hom.: 2212

Bravo AF: 0.496

Asia WGS AF: 0.685 AC: 2383 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	6.4
DANN	Benign	0.63
PhyloP100		-0.095
PromoterAI		-0.059	Neutral
Mutation Taster		=100/0	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: rs35674592; hg19: chr6-29794956;