6-31356423-G-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_005514.8(HLA-B):c.363C>G(p.Ser121Arg) 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. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S121N) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.35 (4536 hom., cov: 3)
  • Exomes 𝑓: 0.43 (113105 hom.)
  • Failed GnomAD Quality Control
• Consequence: HLA-B NM_005514.8 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.84

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=2.1657443E-6).
• BP6: Variant 6-31356423-G-C is Benign according to our data. Variant chr6-31356423-G-C is described in ClinVar as [Benign]. Clinvar id is 3059612.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.735 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HLA-B	NM_005514.8	c.363C>G	p.Ser121Arg	missense_variant	3/8	ENST00000412585.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HLA-B	ENST00000412585.7	c.363C>G	p.Ser121Arg	missense_variant	3/8		NM_005514.8	P1

Frequencies

GnomAD3 genomes AF: 0.347 AC: 11578 AN: 33360 Hom.: 4534 Cov.: 3

Gnomad AFR AF: 0.370

Gnomad AMI AF: 0.473

Gnomad AMR AF: 0.249

Gnomad ASJ AF: 0.265

Gnomad EAS AF: 0.774

Gnomad SAS AF: 0.317

Gnomad FIN AF: 0.327

Gnomad MID AF: 0.583

Gnomad NFE AF: 0.324

Gnomad OTH AF: 0.343

GnomAD3 exomes AF: 0.710 AC: 125997 AN: 177552 Hom.: 51124 AF XY: 0.710 AC XY: 68480 AN XY: 96486

Gnomad AFR exome AF: 0.712

Gnomad AMR exome AF: 0.736

Gnomad ASJ exome AF: 0.823

Gnomad EAS exome AF: 0.903

Gnomad SAS exome AF: 0.784

Gnomad FIN exome AF: 0.642

Gnomad NFE exome AF: 0.647

Gnomad OTH exome AF: 0.725

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.428 AC: 299975 AN: 701228 Hom.: 113105 Cov.: 14 AF XY: 0.441 AC XY: 154750 AN XY: 350816

Gnomad4 AFR exome AF: 0.563

Gnomad4 AMR exome AF: 0.537

Gnomad4 ASJ exome AF: 0.668

Gnomad4 EAS exome AF: 0.743

Gnomad4 SAS exome AF: 0.727

Gnomad4 FIN exome AF: 0.389

Gnomad4 NFE exome AF: 0.378

Gnomad4 OTH exome AF: 0.448

GnomAD4 genome AF: 0.347 AC: 11584 AN: 33368 Hom.: 4536 Cov.: 3 AF XY: 0.344 AC XY: 5343 AN XY: 15510

Gnomad4 AFR AF: 0.370

Gnomad4 AMR AF: 0.249

Gnomad4 ASJ AF: 0.265

Gnomad4 EAS AF: 0.775

Gnomad4 SAS AF: 0.320

Gnomad4 FIN AF: 0.327

Gnomad4 NFE AF: 0.324

Gnomad4 OTH AF: 0.358

Alfa AF: 0.584 Hom.: 3333

ESP6500AA AF: 0.600 AC: 2178

ESP6500EA AF: 0.596 AC: 4707

ExAC AF: 0.643 AC: 71782

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

HLA-B-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 17, 2020

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.58
Cadd	Benign	1.1
Dann	Benign	0.51
DEOGEN2	Benign	0.016	T;.;T
Eigen	Benign	-2.1
Eigen_PC	Benign	-2.1
FATHMM_MKL	Benign	0.016	N
LIST_S2	Benign	0.0043	T;T;T
MetaRNN	Benign	0.0000022	T;T;T
MetaSVM	Benign	-0.89	T
MutationTaster	Benign	1.0	P
PROVEAN	Benign	1.1	N;.;N
REVEL	Benign	0.24
Sift	Benign	1.0	T;.;T
Sift4G	Benign	0.70	T;.;T
Polyphen		0.071	B;.;.
Vest4		0.062
MutPred		0.083		Gain of phosphorylation at T118 (P = 0.1034);Gain of phosphorylation at T118 (P = 0.1034);.;
MPC		0.27
ClinPred		0.0014	T
GERP RS		-2.7
Varity_R		0.17
gMVP		0.21

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: rs1140412; hg19: chr6-31324200; COSMIC: COSV69520372; COSMIC: COSV69520372;