6-31356367-T-A

Variant names:

• chr6-31356367-T-A
• rs4997052
• NM_005514.8:c.419A>T

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.419A>T​(p.Tyr140Phe) variant causes a missense 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. 13/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y140S) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.041 (24 hom., cov: 3)
  • Exomes 𝑓: 0.15 (12826 hom.)
  • Failed GnomAD Quality Control
• Consequence: HLA-B NM_005514.8 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -8.15
• Publications: 34 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 (MetaRNN=0.008739829).

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.419A>T	p.Tyr140Phe	missense	Exon 3 of 8	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.419A>T	p.Tyr140Phe	missense	Exon 3 of 8	ENSP00000399168.2
	HLA-B	ENST00000696559.1		c.419A>T	p.Tyr140Phe	missense	Exon 6 of 11	ENSP00000512717.1
	HLA-B	ENST00000696560.1		c.419A>T	p.Tyr140Phe	missense	Exon 5 of 10	ENSP00000512718.1

Frequencies

GnomAD3 genomes AF: 0.0412 AC: 1449 AN: 35150 Hom.: 25 Cov.: 3

Gnomad AFR AF: 0.0457

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0485

Gnomad ASJ AF: 0.200

Gnomad EAS AF: 0.117

Gnomad SAS AF: 0.217

Gnomad FIN AF: 0.0197

Gnomad MID AF: 0.188

Gnomad NFE AF: 0.0267

Gnomad OTH AF: 0.0650

GnomAD2 exomes AF: 0.194 AC: 36537 AN: 187878 AF XY: 0.195

Gnomad AFR exome AF: 0.157

Gnomad AMR exome AF: 0.281

Gnomad ASJ exome AF: 0.446

Gnomad EAS exome AF: 0.207

Gnomad FIN exome AF: 0.152

Gnomad NFE exome AF: 0.145

Gnomad OTH exome AF: 0.206

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.150 AC: 127416 AN: 850382 Hom.: 12826 Cov.: 17 AF XY: 0.156 AC XY: 66620 AN XY: 426726

African (AFR) AF: 0.175 AC: 3224 AN: 18378

American (AMR) AF: 0.217 AC: 5635 AN: 25920

Ashkenazi Jewish (ASJ) AF: 0.355 AC: 4120 AN: 11604

East Asian (EAS) AF: 0.147 AC: 3543 AN: 24140

South Asian (SAS) AF: 0.278 AC: 15613 AN: 56068

European-Finnish (FIN) AF: 0.104 AC: 2914 AN: 28034

Middle Eastern (MID) AF: 0.315 AC: 685 AN: 2176

European-Non Finnish (NFE) AF: 0.132 AC: 86156 AN: 650498

Other (OTH) AF: 0.165 AC: 5526 AN: 33564

GnomAD4 genome AF: 0.0414 AC: 1454 AN: 35160 Hom.: 24 Cov.: 3 AF XY: 0.0419 AC XY: 698 AN XY: 16668

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

African (AFR) AF: 0.0459 AC: 363 AN: 7902

American (AMR) AF: 0.0490 AC: 145 AN: 2962

Ashkenazi Jewish (ASJ) AF: 0.200 AC: 66 AN: 330

East Asian (EAS) AF: 0.118 AC: 142 AN: 1206

South Asian (SAS) AF: 0.214 AC: 146 AN: 682

European-Finnish (FIN) AF: 0.0197 AC: 50 AN: 2544

Middle Eastern (MID) AF: 0.206 AC: 7 AN: 34

European-Non Finnish (NFE) AF: 0.0267 AC: 508 AN: 19000

Other (OTH) AF: 0.0746 AC: 27 AN: 362

⚠️ 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: 0.183 Hom.: 295

ExAC AF: 0.202 AC: 24019

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	0.0020
DANN	Benign	0.28
DEOGEN2	Benign	0.019	T
Eigen	Benign	-3.3
Eigen_PC	Benign	-3.3
FATHMM_MKL	Benign	0.0038	N
LIST_S2	Benign	0.0094	T
MetaRNN	Benign	0.0087	T
MetaSVM	Benign	-0.97	T
PhyloP100		-8.1
PROVEAN	Benign	-0.60	N
REVEL	Benign	0.23
Sift	Benign	0.55	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.079
MPC		0.20
ClinPred		0.0062	T
GERP RS		-6.4
Varity_R		0.22
gMVP		0.058
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs4997052; hg19: chr6-31324144; COSMIC: COSV69520463; COSMIC: COSV69520463;