chr6-31357118-G-C

Position:

• chr6-31357118-G-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005514.8(HLA-B):​c.41C>G​(p.Ser14Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 11/18 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 nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• 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

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=4.1523576E-4).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.117 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HLA-B	NM_005514.8	c.41C>G	p.Ser14Trp	missense_variant	1/8	ENST00000412585.7	NP_005505.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HLA-B	ENST00000412585.7	c.41C>G	p.Ser14Trp	missense_variant	1/8		NM_005514.8	ENSP00000399168	P1
	ENST00000603274.1	n.472G>C		non_coding_transcript_exon_variant	1/1

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

GnomAD3 exomes AF: 0.298 AC: 41993 AN: 141104 Hom.: 14641 AF XY: 0.313 AC XY: 23849 AN XY: 76304

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 SAS exome AF: 0.553

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

Gnomad4 AFR exome AF: 0.111

Gnomad4 AMR exome AF: 0.0577

Gnomad4 ASJ exome AF: 0.0552

Gnomad4 EAS exome AF: 0.265

Gnomad4 SAS exome AF: 0.189

Gnomad4 FIN exome AF: 0.0409

Gnomad4 NFE exome AF: 0.0261

Gnomad4 OTH exome AF: 0.0527

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

Gnomad4 AFR AF: 0.122

Gnomad4 AMR AF: 0.0468

Gnomad4 ASJ AF: 0.0357

Gnomad4 EAS AF: 0.111

Gnomad4 SAS AF: 0.0753

Gnomad4 FIN AF: 0.0304

Gnomad4 NFE AF: 0.0550

Gnomad4 OTH AF: 0.0889

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
MutationTaster	Benign	1.0	P
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
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.050
gMVP		0.20

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

Publications

LitVar

Other links and lift over

dbSNP: rs1131156; hg19: chr6-31324895; COSMIC: COSV69520786; COSMIC: COSV69520786;