rs3819294

Variant names:

• chr6-31354710-G-A
• rs3819294
• NM_005514.8:c.1013-45C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005514.8(HLA-B):​c.1013-45C>T 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 0.027 (49 hom., cov: 8)
  • Exomes 𝑓: 0.072 (3878 hom.)
• Consequence: HLA-B NM_005514.8 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.40
• Publications: 20 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAdExome4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.155 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005514.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HLA-B	NM_005514.8	MANE Select	c.1013-45C>T		intron	N/A	NP_005505.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HLA-B	ENST00000412585.7	TSL:6 MANE Select	c.1013-45C>T		intron	N/A	ENSP00000399168.2
	HLA-B	ENST00000481849.6	TSL:6	n.2975C>T		non_coding_transcript_exon	Exon 6 of 8
	HLA-B	ENST00000497377.6	TSL:6	n.2882C>T		non_coding_transcript_exon	Exon 7 of 9

Frequencies

GnomAD3 genomes AF: 0.0274 AC: 1646 AN: 60038 Hom.: 49 Cov.: 8

Gnomad AFR AF: 0.0375

Gnomad AMI AF: 0.00195

Gnomad AMR AF: 0.0191

Gnomad ASJ AF: 0.00909

Gnomad EAS AF: 0.0902

Gnomad SAS AF: 0.0239

Gnomad FIN AF: 0.0298

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0220

Gnomad OTH AF: 0.0310

GnomAD2 exomes AF: 0.101 AC: 25227 AN: 250986 AF XY: 0.0965

Gnomad AFR exome AF: 0.136

Gnomad AMR exome AF: 0.0867

Gnomad ASJ exome AF: 0.0207

Gnomad EAS exome AF: 0.254

Gnomad FIN exome AF: 0.138

Gnomad NFE exome AF: 0.0816

Gnomad OTH exome AF: 0.0906

GnomAD4 exome AF: 0.0724 AC: 69924 AN: 966006 Hom.: 3878 Cov.: 13 AF XY: 0.0713 AC XY: 35160 AN XY: 493118

African (AFR) AF: 0.121 AC: 2761 AN: 22884

American (AMR) AF: 0.0798 AC: 3023 AN: 37892

Ashkenazi Jewish (ASJ) AF: 0.0191 AC: 352 AN: 18388

East Asian (EAS) AF: 0.159 AC: 3431 AN: 21512

South Asian (SAS) AF: 0.0723 AC: 5365 AN: 74248

European-Finnish (FIN) AF: 0.104 AC: 3817 AN: 36876

Middle Eastern (MID) AF: 0.0408 AC: 132 AN: 3232

European-Non Finnish (NFE) AF: 0.0680 AC: 48400 AN: 711824

Other (OTH) AF: 0.0675 AC: 2643 AN: 39150

GnomAD4 genome AF: 0.0275 AC: 1651 AN: 60066 Hom.: 49 Cov.: 8 AF XY: 0.0288 AC XY: 816 AN XY: 28286

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

African (AFR) AF: 0.0377 AC: 458 AN: 12156

American (AMR) AF: 0.0191 AC: 85 AN: 4442

Ashkenazi Jewish (ASJ) AF: 0.00909 AC: 16 AN: 1760

East Asian (EAS) AF: 0.0907 AC: 196 AN: 2162

South Asian (SAS) AF: 0.0241 AC: 24 AN: 996

European-Finnish (FIN) AF: 0.0298 AC: 116 AN: 3890

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 96

European-Non Finnish (NFE) AF: 0.0220 AC: 734 AN: 33396

Other (OTH) AF: 0.0320 AC: 21 AN: 656

⚠️ 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: 0.0966 Hom.: 1095

Asia WGS AF: 0.154 AC: 536 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	3.0
DANN	Benign	0.28
PhyloP100		-2.4
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: rs3819294; hg19: chr6-31322487; COSMIC: COSV107515816; COSMIC: COSV107515816;