6-31356889-A-T

Variant names:

• chr6-31356889-A-T
• rs713031
• NM_005514.8:c.142T>A

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.142T>A​(p.Ser48Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.040 (107 hom., cov: 6)
  • Exomes 𝑓: 0.085 (14356 hom.)
  • Failed GnomAD Quality Control
• Consequence: HLA-B NM_005514.8 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.74
• 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]

ENSG00000271581 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.003454417).

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.142T>A	p.Ser48Thr	missense	Exon 2 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.142T>A	p.Ser48Thr	missense	Exon 2 of 8	ENSP00000399168.2
	HLA-B	ENST00000696559.1		c.142T>A	p.Ser48Thr	missense	Exon 5 of 11	ENSP00000512717.1
	HLA-B	ENST00000696560.1		c.142T>A	p.Ser48Thr	missense	Exon 4 of 10	ENSP00000512718.1

Frequencies

GnomAD3 genomes AF: 0.0398 AC: 1874 AN: 47074 Hom.: 109 Cov.: 6

Gnomad AFR AF: 0.0167

Gnomad AMI AF: 0.0430

Gnomad AMR AF: 0.0259

Gnomad ASJ AF: 0.0259

Gnomad EAS AF: 0.135

Gnomad SAS AF: 0.0372

Gnomad FIN AF: 0.0375

Gnomad MID AF: 0.0682

Gnomad NFE AF: 0.0510

Gnomad OTH AF: 0.0504

GnomAD2 exomes AF: 0.144 AC: 27432 AN: 190526 AF XY: 0.146

Gnomad AFR exome AF: 0.0635

Gnomad AMR exome AF: 0.147

Gnomad ASJ exome AF: 0.0823

Gnomad EAS exome AF: 0.204

Gnomad FIN exome AF: 0.160

Gnomad NFE exome AF: 0.135

Gnomad OTH exome AF: 0.172

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0849 AC: 74048 AN: 872498 Hom.: 14356 Cov.: 21 AF XY: 0.0877 AC XY: 38303 AN XY: 436780

African (AFR) AF: 0.0507 AC: 995 AN: 19608

American (AMR) AF: 0.0781 AC: 2278 AN: 29160

Ashkenazi Jewish (ASJ) AF: 0.0516 AC: 947 AN: 18350

East Asian (EAS) AF: 0.152 AC: 3565 AN: 23494

South Asian (SAS) AF: 0.125 AC: 6405 AN: 51152

European-Finnish (FIN) AF: 0.0896 AC: 2695 AN: 30092

Middle Eastern (MID) AF: 0.119 AC: 286 AN: 2408

European-Non Finnish (NFE) AF: 0.0811 AC: 53603 AN: 660966

Other (OTH) AF: 0.0879 AC: 3274 AN: 37268

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0397 AC: 1872 AN: 47122 Hom.: 107 Cov.: 6 AF XY: 0.0366 AC XY: 804 AN XY: 21996

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

African (AFR) AF: 0.0168 AC: 200 AN: 11934

American (AMR) AF: 0.0259 AC: 116 AN: 4472

Ashkenazi Jewish (ASJ) AF: 0.0259 AC: 41 AN: 1584

East Asian (EAS) AF: 0.133 AC: 136 AN: 1020

South Asian (SAS) AF: 0.0346 AC: 31 AN: 896

European-Finnish (FIN) AF: 0.0375 AC: 112 AN: 2990

Middle Eastern (MID) AF: 0.0732 AC: 6 AN: 82

European-Non Finnish (NFE) AF: 0.0510 AC: 1192 AN: 23358

Other (OTH) AF: 0.0509 AC: 27 AN: 530

⚠️ 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: 0.184 Hom.: 936

ExAC AF: 0.142 AC: 16797

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	1.6
DANN	Benign	0.27
DEOGEN2	Benign	0.022	T
Eigen	Benign	-2.2
Eigen_PC	Benign	-2.3
FATHMM_MKL	Benign	0.0073	N
LIST_S2	Benign	0.0027	T
MetaRNN	Benign	0.0035	T
MetaSVM	Benign	-1.0	T
PhyloP100		-2.7
PROVEAN	Benign	-0.78	N
REVEL	Uncertain	0.32
Sift	Benign	0.33	T
Sift4G	Benign	0.15	T
Polyphen		0.0	B
Vest4		0.046
MPC		0.20
ClinPred		0.0024	T
GERP RS		-6.4
PromoterAI		0.0050	Neutral
Varity_R		0.13
gMVP		0.18
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs713031; hg19: chr6-31324666; COSMIC: COSV69520355; COSMIC: COSV69520355;