6-31355632-T-C

Variant names:

• chr6-31355632-T-C
• rs2523605
• NM_005514.8:c.620-40A>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.620-40A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. 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 0.65 (12111 hom., cov: 8)
  • Exomes 𝑓: 0.78 (336672 hom.)
  • Failed GnomAD Quality Control
• Consequence: HLA-B NM_005514.8 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.11
• Publications: 19 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]

ENSG00000298396 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HLA-B	NM_005514.8	c.620-40A>G		intron_variant	Intron 3 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.620-40A>G		intron_variant	Intron 3 of 7	6	NM_005514.8	ENSP00000399168.2

Frequencies

GnomAD3 genomes AF: 0.651 AC: 32187 AN: 49434 Hom.: 12071 Cov.: 8

Gnomad AFR AF: 0.685

Gnomad AMI AF: 0.787

Gnomad AMR AF: 0.701

Gnomad ASJ AF: 0.876

Gnomad EAS AF: 0.591

Gnomad SAS AF: 0.775

Gnomad FIN AF: 0.593

Gnomad MID AF: 0.840

Gnomad NFE AF: 0.625

Gnomad OTH AF: 0.702

GnomAD2 exomes AF: 0.850 AC: 212330 AN: 249770 AF XY: 0.855

Gnomad AFR exome AF: 0.888

Gnomad AMR exome AF: 0.908

Gnomad ASJ exome AF: 0.949

Gnomad EAS exome AF: 0.804

Gnomad FIN exome AF: 0.802

Gnomad NFE exome AF: 0.814

Gnomad OTH exome AF: 0.868

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.778 AC: 763767 AN: 982264 Hom.: 336672 Cov.: 20 AF XY: 0.785 AC XY: 388838 AN XY: 495138

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

African (AFR) AF: 0.866 AC: 18984 AN: 21912

American (AMR) AF: 0.900 AC: 30619 AN: 34004

Ashkenazi Jewish (ASJ) AF: 0.945 AC: 16980 AN: 17960

East Asian (EAS) AF: 0.835 AC: 26722 AN: 31998

South Asian (SAS) AF: 0.928 AC: 65130 AN: 70162

European-Finnish (FIN) AF: 0.767 AC: 30667 AN: 39972

Middle Eastern (MID) AF: 0.922 AC: 3101 AN: 3364

European-Non Finnish (NFE) AF: 0.746 AC: 538211 AN: 721668

Other (OTH) AF: 0.809 AC: 33353 AN: 41224

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.652 AC: 32266 AN: 49510 Hom.: 12111 Cov.: 8 AF XY: 0.643 AC XY: 14899 AN XY: 23160

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

African (AFR) AF: 0.686 AC: 7230 AN: 10534

American (AMR) AF: 0.702 AC: 2779 AN: 3958

Ashkenazi Jewish (ASJ) AF: 0.876 AC: 895 AN: 1022

East Asian (EAS) AF: 0.592 AC: 990 AN: 1672

South Asian (SAS) AF: 0.780 AC: 803 AN: 1030

European-Finnish (FIN) AF: 0.593 AC: 2217 AN: 3740

Middle Eastern (MID) AF: 0.830 AC: 83 AN: 100

European-Non Finnish (NFE) AF: 0.625 AC: 16625 AN: 26582

Other (OTH) AF: 0.711 AC: 397 AN: 558

⚠️ 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: 0.836 Hom.: 21375

Asia WGS AF: 0.902 AC: 3137 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	6.2
DANN	Benign	0.57
PhyloP100		-3.1
PromoterAI		0.013	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: rs2523605; hg19: chr6-31323409;