chr6-31357052-G-C

Variant names:

• chr6-31357052-G-C
• rs9266196
• NM_005514.8:c.73+34C>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_005514.8(HLA-B):​c.73+34C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. There is a variant allele frequency bias in the population database for this variant (GnomAd4), which may indicate mosaicism or somatic mutations in the reference population data. 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 0.056 (327 hom., cov: 3)
  • Exomes 𝑓: 0.12 (39799 hom.)
  • Failed GnomAD Quality Control
• Consequence: HLA-B NM_005514.8 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.231
• Publications: 10 publications found

Genes affected

HLA-B (HGNC:4932): (major histocompatibility complex, class I, B) HLA-B 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. Class I molecules play a central role in the immune system by presenting peptides derived from the endoplasmic reticulum lumen. They are expressed in nearly all cells. The heavy chain is approximately 45 kDa and its gene contains 8 exons. Exon 1 encodes the leader peptide, exon 2 and 3 encode the alpha1 and alpha2 domains, which both bind the peptide, exon 4 encodes the alpha3 domain, exon 5 encodes the transmembrane region and exons 6 and 7 encode the cytoplasmic tail. Polymorphisms within exon 2 and exon 3 are responsible for the peptide binding specificity of each class one molecule. Typing for these polymorphisms is routinely done for bone marrow and kidney transplantation. Hundreds of HLA-B alleles have been described. [provided by RefSeq, Jul 2008]

ENSG00000271581 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HLA-B	NM_005514.8	c.73+34C>G		intron_variant	Intron 1 of 7	ENST00000412585.7	NP_005505.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HLA-B	ENST00000412585.7	c.73+34C>G		intron_variant	Intron 1 of 7	6	NM_005514.8	ENSP00000399168.2

Frequencies

GnomAD3 genomes AF: 0.0559 AC: 2350 AN: 42020 Hom.: 326 Cov.: 3

Gnomad AFR AF: 0.0415

Gnomad AMI AF: 0.0444

Gnomad AMR AF: 0.0489

Gnomad ASJ AF: 0.0474

Gnomad EAS AF: 0.248

Gnomad SAS AF: 0.120

Gnomad FIN AF: 0.0246

Gnomad MID AF: 0.222

Gnomad NFE AF: 0.0596

Gnomad OTH AF: 0.0698

GnomAD2 exomes AF: 0.637 AC: 95424 AN: 149916 AF XY: 0.645

Gnomad AFR exome AF: 0.693

Gnomad AMR exome AF: 0.631

Gnomad ASJ exome AF: 0.533

Gnomad EAS exome AF: 0.886

Gnomad FIN exome AF: 0.616

Gnomad NFE exome AF: 0.542

Gnomad OTH exome AF: 0.638

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.122 AC: 87109 AN: 714552 Hom.: 39799 Cov.: 16 AF XY: 0.134 AC XY: 47778 AN XY: 355824

African (AFR) AF: 0.162 AC: 2172 AN: 13436

American (AMR) AF: 0.166 AC: 3599 AN: 21632

Ashkenazi Jewish (ASJ) AF: 0.147 AC: 2147 AN: 14556

East Asian (EAS) AF: 0.556 AC: 8465 AN: 15236

South Asian (SAS) AF: 0.447 AC: 17255 AN: 38612

European-Finnish (FIN) AF: 0.148 AC: 3389 AN: 22840

Middle Eastern (MID) AF: 0.289 AC: 485 AN: 1678

European-Non Finnish (NFE) AF: 0.0813 AC: 45325 AN: 557420

Other (OTH) AF: 0.147 AC: 4272 AN: 29142

GnomAD4 genome AF: 0.0558 AC: 2347 AN: 42038 Hom.: 327 Cov.: 3 AF XY: 0.0510 AC XY: 1024 AN XY: 20060

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0414 AC: 396 AN: 9556

American (AMR) AF: 0.0489 AC: 193 AN: 3950

Ashkenazi Jewish (ASJ) AF: 0.0474 AC: 65 AN: 1370

East Asian (EAS) AF: 0.249 AC: 178 AN: 716

South Asian (SAS) AF: 0.117 AC: 70 AN: 600

European-Finnish (FIN) AF: 0.0246 AC: 74 AN: 3010

Middle Eastern (MID) AF: 0.200 AC: 10 AN: 50

European-Non Finnish (NFE) AF: 0.0595 AC: 1309 AN: 21994

Other (OTH) AF: 0.0766 AC: 40 AN: 522

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.329 Hom.: 943

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	6.5
DANN	Benign	0.46
PhyloP100		-0.23
PromoterAI		-0.13	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: rs9266196; hg19: chr6-31324829; COSMIC: COSV69520315; COSMIC: COSV69520315;