6-31356716-CA-C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP6_Moderate BS2

The NM_005514.8(HLA-B):c.314del(p.Leu105ArgfsTer46) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. L105L) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.0045 (8 hom., cov: 6)
  • Exomes 𝑓: 0.016 (799 hom.)
  • Failed GnomAD Quality Control
• Consequence: HLA-B NM_005514.8 frameshift
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0870

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]

(HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP6: Variant 6-31356716-CA-C is Benign according to our data. Variant chr6-31356716-CA-C is described in ClinVar as [Likely_benign]. Clinvar id is 3056409.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAdExome at 3497 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HLA-B	NM_005514.8	c.314del	p.Leu105ArgfsTer46	frameshift_variant	2/8	ENST00000412585.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HLA-B	ENST00000412585.7	c.314del	p.Leu105ArgfsTer46	frameshift_variant	2/8		NM_005514.8	P1
	ENST00000603274.1	n.71del		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 247 AN: 54438 Hom.: 8 Cov.: 6 FAILED QC

Gnomad AFR AF: 0.00137

Gnomad AMI AF: 0.00621

Gnomad AMR AF: 0.00200

Gnomad ASJ AF: 0.00620

Gnomad EAS AF: 0.0354

Gnomad SAS AF: 0.0251

Gnomad FIN AF: 0.00299

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00424

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0179 AC: 3497 AN: 195316 Hom.: 229 AF XY: 0.0187 AC XY: 1956 AN XY: 104842

Gnomad AFR exome AF: 0.00791

Gnomad AMR exome AF: 0.00952

Gnomad ASJ exome AF: 0.00574

Gnomad EAS exome AF: 0.0661

Gnomad SAS exome AF: 0.0250

Gnomad FIN exome AF: 0.0122

Gnomad NFE exome AF: 0.0143

Gnomad OTH exome AF: 0.0197

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0161 AC: 15661 AN: 972378 Hom.: 799 Cov.: 29 AF XY: 0.0160 AC XY: 7666 AN XY: 479090

Gnomad4 AFR exome AF: 0.00561

Gnomad4 AMR exome AF: 0.00368

Gnomad4 ASJ exome AF: 0.00566

Gnomad4 EAS exome AF: 0.0301

Gnomad4 SAS exome AF: 0.0199

Gnomad4 FIN exome AF: 0.00212

Gnomad4 NFE exome AF: 0.0171

Gnomad4 OTH exome AF: 0.0160

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00453 AC: 247 AN: 54494 Hom.: 8 Cov.: 6 AF XY: 0.00482 AC XY: 126 AN XY: 26164

Gnomad4 AFR AF: 0.00136

Gnomad4 AMR AF: 0.00200

Gnomad4 ASJ AF: 0.00620

Gnomad4 EAS AF: 0.0354

Gnomad4 SAS AF: 0.0250

Gnomad4 FIN AF: 0.00299

Gnomad4 NFE AF: 0.00424

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

HLA-B-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 17, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs576010607; hg19: chr6-31324493; COSMIC: COSV69521797; COSMIC: COSV69521797;