rs1050683

chr6-31356242-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.544G>A(p.Ala182Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000462 in 51,972 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/18 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 0.00046 (0 hom., cov: 6)
  • Exomes 𝑓: 0.0038 (62 hom.)
  • Failed GnomAD Quality Control
• Consequence: HLA-B NM_005514.8 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.587

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=0.0057958066).
• BS2: High AC in GnomAd at 24 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HLA-B	NM_005514.8	c.544G>A	p.Ala182Thr	missense_variant	3/8	ENST00000412585.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HLA-B	ENST00000412585.7	c.544G>A	p.Ala182Thr	missense_variant	3/8		NM_005514.8	P1

Frequencies

GnomAD3 genomes AF: 0.000462 AC: 24 AN: 51966 Hom.: 0 Cov.: 6

Gnomad AFR AF: 0.000355

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000707

Gnomad ASJ AF: 0.00175

Gnomad EAS AF: 0.000488

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000540

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00595 AC: 1397 AN: 234822 Hom.: 82 AF XY: 0.00513 AC XY: 658 AN XY: 128330

Gnomad AFR exome AF: 0.00189

Gnomad AMR exome AF: 0.0224

Gnomad ASJ exome AF: 0.00990

Gnomad EAS exome AF: 0.0143

Gnomad SAS exome AF: 0.00211

Gnomad FIN exome AF: 0.000479

Gnomad NFE exome AF: 0.00206

Gnomad OTH exome AF: 0.00825

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00376 AC: 4612 AN: 1227090 Hom.: 62 Cov.: 25 AF XY: 0.00388 AC XY: 2368 AN XY: 610758

Gnomad4 AFR exome AF: 0.00203

Gnomad4 AMR exome AF: 0.0145

Gnomad4 ASJ exome AF: 0.0207

Gnomad4 EAS exome AF: 0.0135

Gnomad4 SAS exome AF: 0.00449

Gnomad4 FIN exome AF: 0.00639

Gnomad4 NFE exome AF: 0.00249

Gnomad4 OTH exome AF: 0.00547

GnomAD4 genome AF: 0.000462 AC: 24 AN: 51972 Hom.: 0 Cov.: 6 AF XY: 0.000406 AC XY: 10 AN XY: 24642

Gnomad4 AFR AF: 0.000354

Gnomad4 AMR AF: 0.000706

Gnomad4 ASJ AF: 0.00175

Gnomad4 EAS AF: 0.000489

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000540

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00948 Hom.: 7

ExAC AF: 0.00337 AC: 405

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.48
Cadd	Benign	15
Dann	Benign	0.89
DEOGEN2	Benign	0.024	T;.;T
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.95
FATHMM_MKL	Benign	0.045	N
LIST_S2	Benign	0.088	T;T;T
M_CAP	Benign	0.0029	T
MetaRNN	Benign	0.0058	T;T;T
MetaSVM	Benign	-0.93	T
MutationTaster	Benign	1.0	N
PROVEAN	Benign	-1.1	N;.;N
REVEL	Benign	0.13
Sift	Benign	0.25	T;.;T
Sift4G	Benign	0.13	T;.;T
Polyphen		0.0050	B;.;.
Vest4		0.16
MVP		0.067
MPC		0.22
ClinPred		0.021	T
GERP RS		-0.21
Varity_R		0.21
gMVP		0.078

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: rs1050683; hg19: chr6-31324019;