6-31356226-T-G

Position:

• chr6-31356226-T-G

Variant summary

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

The NM_005514.8(HLA-B):​c.560A>C​(p.Glu187Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. E187L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.083 (162 hom., cov: 4)
  • Exomes 𝑓: 0.33 (34938 hom.)
  • Failed GnomAD Quality Control
• Consequence: HLA-B NM_005514.8 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -8.96

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0055871606).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.163 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HLA-B	NM_005514.8	c.560A>C	p.Glu187Ala	missense_variant	3/8	ENST00000412585.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HLA-B	ENST00000412585.7	c.560A>C	p.Glu187Ala	missense_variant	3/8		NM_005514.8	P1

Frequencies

GnomAD3 genomes AF: 0.0833 AC: 2800 AN: 33632 Hom.: 162 Cov.: 4

Gnomad AFR AF: 0.104

Gnomad AMI AF: 0.0833

Gnomad AMR AF: 0.0724

Gnomad ASJ AF: 0.191

Gnomad EAS AF: 0.0616

Gnomad SAS AF: 0.186

Gnomad FIN AF: 0.0323

Gnomad MID AF: 0.194

Gnomad NFE AF: 0.0781

Gnomad OTH AF: 0.122

GnomAD3 exomes AF: 0.347 AC: 58992 AN: 170240 Hom.: 6075 AF XY: 0.354 AC XY: 32886 AN XY: 92970

Gnomad AFR exome AF: 0.322

Gnomad AMR exome AF: 0.339

Gnomad ASJ exome AF: 0.549

Gnomad EAS exome AF: 0.148

Gnomad SAS exome AF: 0.385

Gnomad FIN exome AF: 0.305

Gnomad NFE exome AF: 0.360

Gnomad OTH exome AF: 0.361

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.333 AC: 293181 AN: 880754 Hom.: 34938 Cov.: 17 AF XY: 0.338 AC XY: 150111 AN XY: 443574

Gnomad4 AFR exome AF: 0.304

Gnomad4 AMR exome AF: 0.318

Gnomad4 ASJ exome AF: 0.477

Gnomad4 EAS exome AF: 0.217

Gnomad4 SAS exome AF: 0.418

Gnomad4 FIN exome AF: 0.204

Gnomad4 NFE exome AF: 0.333

Gnomad4 OTH exome AF: 0.331

GnomAD4 genome AF: 0.0832 AC: 2799 AN: 33636 Hom.: 162 Cov.: 4 AF XY: 0.0773 AC XY: 1223 AN XY: 15816

Gnomad4 AFR AF: 0.104

Gnomad4 AMR AF: 0.0722

Gnomad4 ASJ AF: 0.191

Gnomad4 EAS AF: 0.0621

Gnomad4 SAS AF: 0.187

Gnomad4 FIN AF: 0.0323

Gnomad4 NFE AF: 0.0781

Gnomad4 OTH AF: 0.124

Alfa AF: 0.304 Hom.: 515

ExAC AF: 0.312 AC: 37388

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	0.033
DANN	Benign	0.26
DEOGEN2	Benign	0.030	T;.;T
Eigen	Benign	-2.3
Eigen_PC	Benign	-2.5
FATHMM_MKL	Benign	0.0051	N
LIST_S2	Benign	0.0027	T;T;T
MetaRNN	Benign	0.0056	T;T;T
MetaSVM	Benign	-0.92	T
MutationTaster	Benign	1.0	N
PROVEAN	Benign	-1.4	N;.;N
REVEL	Benign	0.22
Sift	Benign	0.10	T;.;T
Sift4G	Benign	0.52	T;.;T
Polyphen		0.0080	B;.;.
Vest4		0.034
MPC		0.25
ClinPred		0.020	T
GERP RS		-6.4
Varity_R		0.53
gMVP		0.28

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: rs2308466; hg19: chr6-31324003; COSMIC: COSV69520451; COSMIC: COSV69520451;