chr6-31357118-G-C

Variant names:

• chr6-31357118-G-C
• rs1131156
• NM_005514.8:c.41C>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.41C>G​(p.Ser14Trp) 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. 12/19 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 0.070 (786 hom., cov: 5)
  • Exomes 𝑓: 0.042 (11850 hom.)
  • Failed GnomAD Quality Control
• Consequence: HLA-B NM_005514.8 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0730
• Publications: 27 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=4.1523576E-4).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HLA-B	NM_005514.8	c.41C>G	p.Ser14Trp	missense_variant	Exon 1 of 8	ENST00000412585.7	NP_005505.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HLA-B	ENST00000412585.7	c.41C>G	p.Ser14Trp	missense_variant	Exon 1 of 8	6	NM_005514.8	ENSP00000399168.2

Frequencies

GnomAD3 genomes AF: 0.0700 AC: 3695 AN: 52754 Hom.: 779 Cov.: 5

Gnomad AFR AF: 0.122

Gnomad AMI AF: 0.0762

Gnomad AMR AF: 0.0468

Gnomad ASJ AF: 0.0357

Gnomad EAS AF: 0.111

Gnomad SAS AF: 0.0766

Gnomad FIN AF: 0.0304

Gnomad MID AF: 0.0833

Gnomad NFE AF: 0.0550

Gnomad OTH AF: 0.0754

GnomAD2 exomes AF: 0.298 AC: 41993 AN: 141104 AF XY: 0.313

Gnomad AFR exome AF: 0.354

Gnomad AMR exome AF: 0.332

Gnomad ASJ exome AF: 0.305

Gnomad EAS exome AF: 0.332

Gnomad FIN exome AF: 0.205

Gnomad NFE exome AF: 0.211

Gnomad OTH exome AF: 0.307

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0419 AC: 32860 AN: 784172 Hom.: 11850 Cov.: 23 AF XY: 0.0469 AC XY: 18141 AN XY: 386656

African (AFR) AF: 0.111 AC: 1667 AN: 14964

American (AMR) AF: 0.0577 AC: 1349 AN: 23370

Ashkenazi Jewish (ASJ) AF: 0.0552 AC: 870 AN: 15760

East Asian (EAS) AF: 0.265 AC: 3596 AN: 13568

South Asian (SAS) AF: 0.189 AC: 6205 AN: 32856

European-Finnish (FIN) AF: 0.0409 AC: 1009 AN: 24700

Middle Eastern (MID) AF: 0.0812 AC: 173 AN: 2130

European-Non Finnish (NFE) AF: 0.0261 AC: 16306 AN: 624830

Other (OTH) AF: 0.0527 AC: 1685 AN: 31994

GnomAD4 genome AF: 0.0702 AC: 3703 AN: 52768 Hom.: 786 Cov.: 5 AF XY: 0.0664 AC XY: 1670 AN XY: 25158

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

African (AFR) AF: 0.122 AC: 1577 AN: 12962

American (AMR) AF: 0.0468 AC: 234 AN: 5004

Ashkenazi Jewish (ASJ) AF: 0.0357 AC: 58 AN: 1624

East Asian (EAS) AF: 0.111 AC: 104 AN: 940

South Asian (SAS) AF: 0.0753 AC: 58 AN: 770

European-Finnish (FIN) AF: 0.0304 AC: 111 AN: 3650

Middle Eastern (MID) AF: 0.0811 AC: 6 AN: 74

European-Non Finnish (NFE) AF: 0.0550 AC: 1471 AN: 26756

Other (OTH) AF: 0.0889 AC: 61 AN: 686

⚠️ 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: 0.303 Hom.: 1807

ESP6500AA AF: 0.292 AC: 1201

ESP6500EA AF: 0.224 AC: 1790

ExAC AF: 0.363 AC: 41423

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	21
DANN	Benign	0.63
DEOGEN2	Benign	0.041	T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.013	N
LIST_S2	Benign	0.60	T;T
MetaRNN	Benign	0.00042	T;T
MetaSVM	Benign	-0.96	T
PhyloP100		-0.073
PROVEAN	Uncertain	-2.8	D;.
REVEL	Benign	0.26
Sift	Benign	0.30	T;.
Sift4G	Uncertain	0.022	D;.
Polyphen		0.0	B;.
Vest4		0.14
MPC		0.98
ClinPred		0.035	T
GERP RS		1.5
PromoterAI		-0.080	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.050
gMVP		0.20
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1131156; hg19: chr6-31324895; COSMIC: COSV69520786; COSMIC: COSV69520786;