NM_005514.8:c.277G>A

Variant names:

• chr6-31356754-C-T
• rs1131204
• NM_005514.8:c.277G>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_005514.8(HLA-B):​c.277G>A​(p.Ala93Thr) 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. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars). Synonymous variant affecting the same amino acid position (i.e. A93A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.43 (5437 hom., cov: 5)
  • Exomes 𝑓: 0.66 (264581 hom.)
  • Failed GnomAD Quality Control
• Consequence: HLA-B NM_005514.8 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: -3.32
• Publications: 30 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 -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=2.3709429E-6).
• BP6: Variant 6-31356754-C-T is Benign according to our data. Variant chr6-31356754-C-T is described in ClinVar as Benign. ClinVar VariationId is 3061033.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005514.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HLA-B	NM_005514.8	MANE Select	c.277G>A	p.Ala93Thr	missense	Exon 2 of 8	NP_005505.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HLA-B	ENST00000412585.7	TSL:6 MANE Select	c.277G>A	p.Ala93Thr	missense	Exon 2 of 8	ENSP00000399168.2
	HLA-B	ENST00000696559.1		c.277G>A	p.Ala93Thr	missense	Exon 5 of 11	ENSP00000512717.1
	HLA-B	ENST00000696560.1		c.277G>A	p.Ala93Thr	missense	Exon 4 of 10	ENSP00000512718.1

Frequencies

GnomAD3 genomes AF: 0.432 AC: 15957 AN: 36896 Hom.: 5432 Cov.: 5

Gnomad AFR AF: 0.284

Gnomad AMI AF: 0.636

Gnomad AMR AF: 0.597

Gnomad ASJ AF: 0.825

Gnomad EAS AF: 0.521

Gnomad SAS AF: 0.466

Gnomad FIN AF: 0.426

Gnomad MID AF: 0.733

Gnomad NFE AF: 0.438

Gnomad OTH AF: 0.471

GnomAD2 exomes AF: 0.766 AC: 149551 AN: 195270 AF XY: 0.768

Gnomad AFR exome AF: 0.655

Gnomad AMR exome AF: 0.898

Gnomad ASJ exome AF: 0.874

Gnomad EAS exome AF: 0.720

Gnomad FIN exome AF: 0.738

Gnomad NFE exome AF: 0.720

Gnomad OTH exome AF: 0.766

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.662 AC: 600088 AN: 907044 Hom.: 264581 Cov.: 18 AF XY: 0.666 AC XY: 300379 AN XY: 450786

African (AFR) AF: 0.512 AC: 8673 AN: 16950

American (AMR) AF: 0.858 AC: 25983 AN: 30292

Ashkenazi Jewish (ASJ) AF: 0.873 AC: 15544 AN: 17812

East Asian (EAS) AF: 0.635 AC: 12951 AN: 20410

South Asian (SAS) AF: 0.785 AC: 40902 AN: 52124

European-Finnish (FIN) AF: 0.588 AC: 16847 AN: 28658

Middle Eastern (MID) AF: 0.778 AC: 1946 AN: 2502

European-Non Finnish (NFE) AF: 0.645 AC: 452382 AN: 701698

Other (OTH) AF: 0.679 AC: 24860 AN: 36598

GnomAD4 genome AF: 0.433 AC: 15979 AN: 36942 Hom.: 5437 Cov.: 5 AF XY: 0.426 AC XY: 7462 AN XY: 17512

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

African (AFR) AF: 0.285 AC: 2549 AN: 8954

American (AMR) AF: 0.598 AC: 2024 AN: 3386

Ashkenazi Jewish (ASJ) AF: 0.825 AC: 1043 AN: 1264

East Asian (EAS) AF: 0.521 AC: 537 AN: 1030

South Asian (SAS) AF: 0.470 AC: 280 AN: 596

European-Finnish (FIN) AF: 0.426 AC: 1024 AN: 2404

Middle Eastern (MID) AF: 0.741 AC: 40 AN: 54

European-Non Finnish (NFE) AF: 0.438 AC: 8155 AN: 18626

Other (OTH) AF: 0.467 AC: 201 AN: 430

⚠️ 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: 0.641 Hom.: 3628

ESP6500AA AF: 0.632 AC: 2616

ESP6500EA AF: 0.656 AC: 5337

ExAC AF: 0.694 AC: 82387

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	HLA-B-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	5.0
DANN	Benign	0.84
DEOGEN2	Benign	0.020	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.0068	N
LIST_S2	Benign	0.045	T
MetaRNN	Benign	0.0000024	T
MetaSVM	Benign	-1.0	T
PhyloP100		-3.3
PROVEAN	Benign	-0.44	N
REVEL	Benign	0.29
Sift	Benign	0.52	T
Sift4G	Benign	0.37	T
Polyphen		0.0	B
Vest4		0.047
MPC		0.22
ClinPred		0.00033	T
GERP RS		-2.7
PromoterAI		-0.16	Neutral
Varity_R		0.066
gMVP		0.047
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1131204; hg19: chr6-31324531; COSMIC: COSV69520472; COSMIC: COSV69520472;