6-31356889-A-C

Variant names:

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

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>G​(p.Ser48Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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.

• Frequency:
  • Genomes: 𝑓 0.19 (1772 hom., cov: 6)
  • Exomes 𝑓: 0.17 (44219 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=0.0013540089).

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>G	p.Ser48Ala	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>G	p.Ser48Ala	missense	Exon 2 of 8	ENSP00000399168.2
	HLA-B	ENST00000696559.1		c.142T>G	p.Ser48Ala	missense	Exon 5 of 11	ENSP00000512717.1
	HLA-B	ENST00000696560.1		c.142T>G	p.Ser48Ala	missense	Exon 4 of 10	ENSP00000512718.1

Frequencies

GnomAD3 genomes AF: 0.190 AC: 8907 AN: 46828 Hom.: 1765 Cov.: 6

Gnomad AFR AF: 0.197

Gnomad AMI AF: 0.198

Gnomad AMR AF: 0.253

Gnomad ASJ AF: 0.233

Gnomad EAS AF: 0.393

Gnomad SAS AF: 0.389

Gnomad FIN AF: 0.201

Gnomad MID AF: 0.442

Gnomad NFE AF: 0.154

Gnomad OTH AF: 0.206

GnomAD2 exomes AF: 0.442 AC: 84226 AN: 190526 AF XY: 0.450

Gnomad AFR exome AF: 0.461

Gnomad AMR exome AF: 0.440

Gnomad ASJ exome AF: 0.420

Gnomad EAS exome AF: 0.643

Gnomad FIN exome AF: 0.452

Gnomad NFE exome AF: 0.370

Gnomad OTH exome AF: 0.417

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.173 AC: 155452 AN: 896142 Hom.: 44219 Cov.: 21 AF XY: 0.182 AC XY: 81647 AN XY: 447620

African (AFR) AF: 0.238 AC: 4431 AN: 18640

American (AMR) AF: 0.263 AC: 7352 AN: 27978

Ashkenazi Jewish (ASJ) AF: 0.284 AC: 4990 AN: 17576

East Asian (EAS) AF: 0.536 AC: 12510 AN: 23354

South Asian (SAS) AF: 0.404 AC: 19988 AN: 49444

European-Finnish (FIN) AF: 0.238 AC: 7152 AN: 30004

Middle Eastern (MID) AF: 0.355 AC: 852 AN: 2402

European-Non Finnish (NFE) AF: 0.131 AC: 90575 AN: 689088

Other (OTH) AF: 0.202 AC: 7602 AN: 37656

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.191 AC: 8932 AN: 46882 Hom.: 1772 Cov.: 6 AF XY: 0.191 AC XY: 4147 AN XY: 21728

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

African (AFR) AF: 0.197 AC: 2244 AN: 11372

American (AMR) AF: 0.252 AC: 1099 AN: 4366

Ashkenazi Jewish (ASJ) AF: 0.233 AC: 370 AN: 1586

East Asian (EAS) AF: 0.396 AC: 409 AN: 1034

South Asian (SAS) AF: 0.392 AC: 335 AN: 854

European-Finnish (FIN) AF: 0.201 AC: 599 AN: 2982

Middle Eastern (MID) AF: 0.439 AC: 36 AN: 82

European-Non Finnish (NFE) AF: 0.154 AC: 3679 AN: 23850

Other (OTH) AF: 0.220 AC: 113 AN: 514

⚠️ 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: 0.266 Hom.: 936

ESP6500AA AF: 0.461 AC: 1957

ESP6500EA AF: 0.387 AC: 3187

ExAC AF: 0.440 AC: 52034

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.057
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	1.6
DANN	Benign	0.17
DEOGEN2	Benign	0.016	T
Eigen	Benign	-2.3
Eigen_PC	Benign	-2.4
FATHMM_MKL	Benign	0.0056	N
LIST_S2	Benign	0.0015	T
MetaRNN	Benign	0.0014	T
MetaSVM	Benign	-1.0	T
PhyloP100		-2.7
PROVEAN	Benign	0.55	N
REVEL	Benign	0.26
Sift	Benign	0.87	T
Sift4G	Benign	0.83	T
Polyphen		0.0	B
Vest4		0.029
MPC		0.18
ClinPred		0.00032	T
GERP RS		-6.4
PromoterAI		0.014	Neutral
Varity_R		0.089
gMVP		0.10
Mutation Taster		=90/10	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: COSV69521350; COSMIC: COSV69521350;