6-31356061-C-G

Variant names:

• chr6-31356061-C-G
• rs2596494
• NM_005514.8:c.619+106G>C

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.619+106G>C 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 0.72 (18080 hom., cov: 9)
  • Exomes 𝑓: 0.39 (61912 hom.)
  • Failed GnomAD Quality Control
• Consequence: HLA-B NM_005514.8 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.11
• Publications: 12 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=-0.89).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HLA-B	NM_005514.8	c.619+106G>C		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.619+106G>C		intron_variant	Intron 3 of 7	6	NM_005514.8	ENSP00000399168.2

Frequencies

GnomAD3 genomes AF: 0.717 AC: 45823 AN: 63928 Hom.: 18035 Cov.: 9

Gnomad AFR AF: 0.767

Gnomad AMI AF: 0.799

Gnomad AMR AF: 0.789

Gnomad ASJ AF: 0.873

Gnomad EAS AF: 0.719

Gnomad SAS AF: 0.828

Gnomad FIN AF: 0.633

Gnomad MID AF: 0.901

Gnomad NFE AF: 0.679

Gnomad OTH AF: 0.762

GnomAD2 exomes AF: 0.845 AC: 129264 AN: 152902 AF XY: 0.850

Gnomad AFR exome AF: 0.874

Gnomad AMR exome AF: 0.907

Gnomad ASJ exome AF: 0.951

Gnomad EAS exome AF: 0.793

Gnomad FIN exome AF: 0.783

Gnomad NFE exome AF: 0.798

Gnomad OTH exome AF: 0.875

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.389 AC: 134026 AN: 344178 Hom.: 61912 Cov.: 4 AF XY: 0.418 AC XY: 74712 AN XY: 178626

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

African (AFR) AF: 0.589 AC: 4237 AN: 7190

American (AMR) AF: 0.670 AC: 8046 AN: 12008

Ashkenazi Jewish (ASJ) AF: 0.692 AC: 3009 AN: 4350

East Asian (EAS) AF: 0.560 AC: 7241 AN: 12920

South Asian (SAS) AF: 0.847 AC: 31168 AN: 36782

European-Finnish (FIN) AF: 0.353 AC: 5105 AN: 14454

Middle Eastern (MID) AF: 0.661 AC: 596 AN: 902

European-Non Finnish (NFE) AF: 0.283 AC: 68285 AN: 240976

Other (OTH) AF: 0.434 AC: 6339 AN: 14596

⚠️ 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: 0.717 AC: 45919 AN: 64026 Hom.: 18080 Cov.: 9 AF XY: 0.712 AC XY: 21405 AN XY: 30044

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

African (AFR) AF: 0.768 AC: 11416 AN: 14872

American (AMR) AF: 0.790 AC: 4687 AN: 5934

Ashkenazi Jewish (ASJ) AF: 0.873 AC: 965 AN: 1106

East Asian (EAS) AF: 0.720 AC: 1587 AN: 2204

South Asian (SAS) AF: 0.829 AC: 1275 AN: 1538

European-Finnish (FIN) AF: 0.633 AC: 2790 AN: 4410

Middle Eastern (MID) AF: 0.894 AC: 118 AN: 132

European-Non Finnish (NFE) AF: 0.679 AC: 22202 AN: 32702

Other (OTH) AF: 0.768 AC: 545 AN: 710

⚠️ 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: 0.806 Hom.: 5045

Asia WGS AF: 0.902 AC: 3138 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	9.1
DANN	Benign	0.31
PhyloP100		-1.1
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: rs2596494; hg19: chr6-31323838; COSMIC: COSV69522605;