rs1131204

chr6-31356754-C-Gchr6-31356754-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.277G>C(p.Ala93Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 10/17 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. A93T) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.00023 (1 hom., cov: 5)
  • Exomes 𝑓: 0.0050 (19 hom.)
  • Failed GnomAD Quality Control
• Consequence: HLA-B NM_005514.8 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.32

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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0027052164).
• BS2: High AC in GnomAdExome at 529 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HLA-B	NM_005514.8	c.277G>C	p.Ala93Pro	missense_variant	2/8	ENST00000412585.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HLA-B	ENST00000412585.7	c.277G>C	p.Ala93Pro	missense_variant	2/8		NM_005514.8	P1
	ENST00000603274.1	n.108C>G		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 10 AN: 43104 Hom.: 1 Cov.: 5 FAILED QC

Gnomad AFR AF: 0.000557

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00272

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000457

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00271 AC: 529 AN: 195270 Hom.: 54 AF XY: 0.00234 AC XY: 250 AN XY: 106720

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0424

Gnomad SAS exome AF: 0.000118

Gnomad FIN exome AF: 0.0000597

Gnomad NFE exome AF: 0.0000232

Gnomad OTH exome AF: 0.00129

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00498 AC: 4804 AN: 965400 Hom.: 19 Cov.: 18 AF XY: 0.00506 AC XY: 2427 AN XY: 479476

Gnomad4 AFR exome AF: 0.00508

Gnomad4 AMR exome AF: 0.00418

Gnomad4 ASJ exome AF: 0.00193

Gnomad4 EAS exome AF: 0.0198

Gnomad4 SAS exome AF: 0.00741

Gnomad4 FIN exome AF: 0.00133

Gnomad4 NFE exome AF: 0.00470

Gnomad4 OTH exome AF: 0.00376

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000232 AC: 10 AN: 43156 Hom.: 1 Cov.: 5 AF XY: 0.000295 AC XY: 6 AN XY: 20360

Gnomad4 AFR AF: 0.000555

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00274

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000457

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000437 Hom.: 3628

ExAC AF: 0.00215 AC: 255

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.55
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.35
Cadd	Benign	7.9
Dann	Benign	0.82
DEOGEN2	Benign	0.047	T;.;T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.019	N
LIST_S2	Benign	0.037	T;T;T
MetaRNN	Benign	0.0027	T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N
PROVEAN	Benign	-1.4	N;.;N
REVEL	Benign	0.23
Sift	Uncertain	0.0030	D;.;D
Sift4G	Benign	0.064	T;.;T
Polyphen		0.60	P;.;.
Vest4		0.27
MVP		0.040
MPC		0.70
ClinPred		0.16	T
GERP RS		-2.7
Varity_R		0.49
gMVP		0.31

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: rs1131204; hg19: chr6-31324531;