rs12697943

chr6-31356280-C-Achr6-31356280-C-Gchr6-31356280-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_005514.8(HLA-B):c.506G>T(p.Arg169Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00172 in 54,068 control chromosomes in the GnomAD database, including 1 homozygotes. 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 0.0017 (1 hom., cov: 6)
  • Exomes 𝑓: 0.0043 (18 hom.)
  • Failed GnomAD Quality Control
• Consequence: HLA-B NM_005514.8 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.494

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]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009438276).
• BS2: High AC in GnomAd at 92 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HLA-B	NM_005514.8	c.506G>T	p.Arg169Leu	missense_variant	3/8	ENST00000412585.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HLA-B	ENST00000412585.7	c.506G>T	p.Arg169Leu	missense_variant	3/8		NM_005514.8	P1

Frequencies

GnomAD3 genomes AF: 0.00170 AC: 92 AN: 54056 Hom.: 1 Cov.: 6

Gnomad AFR AF: 0.000583

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000862

Gnomad ASJ AF: 0.00487

Gnomad EAS AF: 0.00886

Gnomad SAS AF: 0.00347

Gnomad FIN AF: 0.000512

Gnomad MID AF: 0.0114

Gnomad NFE AF: 0.00176

Gnomad OTH AF: 0.00161

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00427 AC: 5536 AN: 1297578 Hom.: 18 Cov.: 34 AF XY: 0.00458 AC XY: 2953 AN XY: 644546

Gnomad4 AFR exome AF: 0.00192

Gnomad4 AMR exome AF: 0.00297

Gnomad4 ASJ exome AF: 0.0120

Gnomad4 EAS exome AF: 0.0165

Gnomad4 SAS exome AF: 0.0105

Gnomad4 FIN exome AF: 0.00796

Gnomad4 NFE exome AF: 0.00311

Gnomad4 OTH exome AF: 0.00525

GnomAD4 genome AF: 0.00172 AC: 93 AN: 54068 Hom.: 1 Cov.: 6 AF XY: 0.00197 AC XY: 51 AN XY: 25902

Gnomad4 AFR AF: 0.000581

Gnomad4 AMR AF: 0.000860

Gnomad4 ASJ AF: 0.00487

Gnomad4 EAS AF: 0.00889

Gnomad4 SAS AF: 0.00351

Gnomad4 FIN AF: 0.000512

Gnomad4 NFE AF: 0.00176

Gnomad4 OTH AF: 0.00314

Alfa AF: 0.00981 Hom.: 8

ExAC AF: 0.0190 AC: 2291

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.096	T
BayesDel_noAF	Benign	-0.38
Cadd	Benign	19
Dann	Benign	0.55
DEOGEN2	Benign	0.016	T;.;T
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.75
FATHMM_MKL	Benign	0.052	N
LIST_S2	Benign	0.037	T;T;T
MetaRNN	Benign	0.0094	T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N
PROVEAN	Pathogenic	-5.5	D;.;D
REVEL	Benign	0.13
Sift	Pathogenic	0.0	D;.;D
Sift4G	Uncertain	0.020	D;.;D
Polyphen		0.0070	B;.;.
Vest4		0.12
MPC		0.93
ClinPred		0.079	T
GERP RS		0.27
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.72
gMVP		0.24

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

Publications

LitVar

Other links and lift over

dbSNP: rs12697943; hg19: chr6-31324057; COSMIC: COSV69521781; COSMIC: COSV69521781;