6-31355013-T-C

Variant names:

• chr6-31355013-T-C
• rs2523607
• NM_005514.8:c.1012+94A>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.1012+94A>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 0.000016 (0 hom., cov: 8)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: HLA-B NM_005514.8 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.45
• Publications: 38 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:):

MIR6891 (HGNC:50243): (microRNA 6891) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HLA-B	NM_005514.8	c.1012+94A>G		intron_variant	Intron 5 of 7	ENST00000412585.7	NP_005505.2
MIR6891	NR_106951.1	n.*211A>G		downstream_gene_variant
MIR6891	unassigned_transcript_1096	n.*215A>G		downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HLA-B	ENST00000412585.7	c.1012+94A>G		intron_variant	Intron 5 of 7	6	NM_005514.8	ENSP00000399168.2

Frequencies

GnomAD3 genomes AF: 0.0000156 AC: 1 AN: 63988 Hom.: 0 Cov.: 8

Gnomad AFR AF: 0.0000765

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 318578 Hom.: 0 Cov.: 4 AF XY: 0.00 AC XY: 0 AN XY: 168732

African (AFR) AF: 0.00 AC: 0 AN: 7788

American (AMR) AF: 0.00 AC: 0 AN: 16936

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 8418

East Asian (EAS) AF: 0.00 AC: 0 AN: 15318

South Asian (SAS) AF: 0.00 AC: 0 AN: 26316

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 22994

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1270

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 203154

Other (OTH) AF: 0.00 AC: 0 AN: 16384

GnomAD4 genome AF: 0.0000156 AC: 1 AN: 63988 Hom.: 0 Cov.: 8 AF XY: 0.0000328 AC XY: 1 AN XY: 30502

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

African (AFR) AF: 0.0000765 AC: 1 AN: 13078

American (AMR) AF: 0.00 AC: 0 AN: 4784

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1758

East Asian (EAS) AF: 0.00 AC: 0 AN: 2386

South Asian (SAS) AF: 0.00 AC: 0 AN: 1186

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 4602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 94

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 34890

Other (OTH) AF: 0.00 AC: 0 AN: 702

⚠️ 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: 0.00 Hom.: 61

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	8.4
DANN	Benign	0.49
PhyloP100		-1.5
PromoterAI		0.0083	Neutral

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: rs2523607; hg19: chr6-31322790;