6-31356889-A-G

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_005514.8(HLA-B):​c.142T>C​(p.Ser48Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 13/20 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 0.000020 (0 hom., cov: 6)
  • Exomes 𝑓: 0.0 (0 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 -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.2019585).

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>C	p.Ser48Pro	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>C	p.Ser48Pro	missense	Exon 2 of 8	ENSP00000399168.2
	HLA-B	ENST00000696559.1		c.142T>C	p.Ser48Pro	missense	Exon 5 of 11	ENSP00000512717.1
	HLA-B	ENST00000696560.1		c.142T>C	p.Ser48Pro	missense	Exon 4 of 10	ENSP00000512718.1

Frequencies

GnomAD3 genomes AF: 0.0000201 AC: 1 AN: 49668 Hom.: 0 Cov.: 6

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00185

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 956894 Hom.: 0 Cov.: 21 AF XY: 0.00 AC XY: 0 AN XY: 477958

African (AFR) AF: 0.00 AC: 0 AN: 20368

American (AMR) AF: 0.00 AC: 0 AN: 31126

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19672

East Asian (EAS) AF: 0.00 AC: 0 AN: 25184

South Asian (SAS) AF: 0.00 AC: 0 AN: 54250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32020

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2628

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 731156

Other (OTH) AF: 0.00 AC: 0 AN: 40490

GnomAD4 genome AF: 0.0000201 AC: 1 AN: 49668 Hom.: 0 Cov.: 6 AF XY: 0.0000434 AC XY: 1 AN XY: 23054

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

African (AFR) AF: 0.00 AC: 0 AN: 12250

American (AMR) AF: 0.00 AC: 0 AN: 4694

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1658

East Asian (EAS) AF: 0.00 AC: 0 AN: 1102

South Asian (SAS) AF: 0.00 AC: 0 AN: 914

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 3166

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 90

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 24988

Other (OTH) AF: 0.00185 AC: 1 AN: 540

⚠️ 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.

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.77
BayesDel_addAF	Benign	-0.045	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	6.9
DANN	Benign	0.47
DEOGEN2	Benign	0.038	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.012	N
LIST_S2	Benign	0.0031	T
M_CAP	Benign	0.00096	T
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-1.1	T
PhyloP100		-2.7
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.27
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.015	D
Polyphen		0.39	B
Vest4		0.38
MVP		0.18
MPC		0.46
ClinPred		0.27	T
GERP RS		-6.4
PromoterAI		-0.039	Neutral
Varity_R		0.70
gMVP		0.64
Mutation Taster		=100/0	polymorphism

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: rs713031; hg19: chr6-31324666;