6-31354590-T-G

Variant names:

• chr6-31354590-T-G
• rs3819299
• NM_005514.8:c.1045+43A>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.1045+43A>C 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 0.023 (33 hom., cov: 12)
  • Exomes 𝑓: 0.048 (2663 hom.)
  • Failed GnomAD Quality Control
• Consequence: HLA-B NM_005514.8 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.288
• Publications: 55 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=-0.84).

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.1045+43A>C		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.1045+43A>C		intron	N/A	ENSP00000399168.2
	HLA-B	ENST00000696559.1		c.1045+43A>C		intron	N/A	ENSP00000512717.1
	HLA-B	ENST00000696560.1		c.1045+43A>C		intron	N/A	ENSP00000512718.1

Frequencies

GnomAD3 genomes AF: 0.0232 AC: 2158 AN: 92946 Hom.: 32 Cov.: 12

Gnomad AFR AF: 0.00823

Gnomad AMI AF: 0.0178

Gnomad AMR AF: 0.0307

Gnomad ASJ AF: 0.0154

Gnomad EAS AF: 0.0331

Gnomad SAS AF: 0.0469

Gnomad FIN AF: 0.0332

Gnomad MID AF: 0.0364

Gnomad NFE AF: 0.0269

Gnomad OTH AF: 0.0160

GnomAD2 exomes AF: 0.0773 AC: 19444 AN: 251434 AF XY: 0.0785

Gnomad AFR exome AF: 0.0155

Gnomad AMR exome AF: 0.107

Gnomad ASJ exome AF: 0.0290

Gnomad EAS exome AF: 0.0685

Gnomad FIN exome AF: 0.117

Gnomad NFE exome AF: 0.0628

Gnomad OTH exome AF: 0.0768

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0482 AC: 64680 AN: 1342570 Hom.: 2663 Cov.: 29 AF XY: 0.0508 AC XY: 33979 AN XY: 668734

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

African (AFR) AF: 0.0106 AC: 330 AN: 31132

American (AMR) AF: 0.0970 AC: 3984 AN: 41086

Ashkenazi Jewish (ASJ) AF: 0.0242 AC: 554 AN: 22878

East Asian (EAS) AF: 0.0793 AC: 2294 AN: 28936

South Asian (SAS) AF: 0.109 AC: 9084 AN: 83054

European-Finnish (FIN) AF: 0.0891 AC: 3932 AN: 44114

Middle Eastern (MID) AF: 0.0359 AC: 186 AN: 5188

European-Non Finnish (NFE) AF: 0.0405 AC: 41829 AN: 1032120

Other (OTH) AF: 0.0460 AC: 2487 AN: 54062

⚠️ 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 AF: 0.0232 AC: 2161 AN: 93004 Hom.: 33 Cov.: 12 AF XY: 0.0226 AC XY: 985 AN XY: 43676

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

African (AFR) AF: 0.00816 AC: 184 AN: 22554

American (AMR) AF: 0.0313 AC: 219 AN: 7004

Ashkenazi Jewish (ASJ) AF: 0.0154 AC: 36 AN: 2332

East Asian (EAS) AF: 0.0336 AC: 108 AN: 3216

South Asian (SAS) AF: 0.0474 AC: 92 AN: 1942

European-Finnish (FIN) AF: 0.0332 AC: 176 AN: 5304

Middle Eastern (MID) AF: 0.0343 AC: 7 AN: 204

European-Non Finnish (NFE) AF: 0.0269 AC: 1309 AN: 48648

Other (OTH) AF: 0.0159 AC: 17 AN: 1070

⚠️ 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: 0.0561 Hom.: 860

Asia WGS AF: 0.126 AC: 439 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	12
DANN	Benign	0.67
PhyloP100		-0.29
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs3819299; hg19: chr6-31322367; COSMIC: COSV69520537; COSMIC: COSV69520537;