6-31356712-C-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_005514.8(HLA-B):c.319G>T(p.Gly107Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G107R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0056 (8 hom., cov: 3)
  • Exomes 𝑓: 0.015 (854 hom.)
  • Failed GnomAD Quality Control
• Consequence: HLA-B NM_005514.8 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.91

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0061599314).
• BP6: Variant 6-31356712-C-A is Benign according to our data. Variant chr6-31356712-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 3056636.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00565 (246/43554) while in subpopulation EAS AF= 0.0446 (58/1300). AF 95% confidence interval is 0.0354. There are 8 homozygotes in gnomad4. There are 119 alleles in male gnomad4 subpopulation. Median coverage is 3. This position pass quality control queck.
• BS2: High AC in GnomAd at 246 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HLA-B	NM_005514.8	c.319G>T	p.Gly107Cys	missense_variant	2/8	ENST00000412585.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HLA-B	ENST00000412585.7	c.319G>T	p.Gly107Cys	missense_variant	2/8		NM_005514.8	P1
	ENST00000603274.1	n.66C>A		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes AF: 0.00565 AC: 246 AN: 43510 Hom.: 8 Cov.: 3

Gnomad AFR AF: 0.00182

Gnomad AMI AF: 0.00382

Gnomad AMR AF: 0.00276

Gnomad ASJ AF: 0.00672

Gnomad EAS AF: 0.0444

Gnomad SAS AF: 0.0297

Gnomad FIN AF: 0.00260

Gnomad MID AF: 0.0147

Gnomad NFE AF: 0.00524

Gnomad OTH AF: 0.00193

GnomAD3 exomes AF: 0.0256 AC: 3831 AN: 149466 Hom.: 263 AF XY: 0.0270 AC XY: 2144 AN XY: 79364

Gnomad AFR exome AF: 0.0117

Gnomad AMR exome AF: 0.0126

Gnomad ASJ exome AF: 0.0101

Gnomad EAS exome AF: 0.0874

Gnomad SAS exome AF: 0.0372

Gnomad FIN exome AF: 0.0161

Gnomad NFE exome AF: 0.0222

Gnomad OTH exome AF: 0.0245

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0154 AC: 16088 AN: 1042756 Hom.: 854 Cov.: 30 AF XY: 0.0151 AC XY: 7836 AN XY: 517484

Gnomad4 AFR exome AF: 0.00530

Gnomad4 AMR exome AF: 0.00340

Gnomad4 ASJ exome AF: 0.00415

Gnomad4 EAS exome AF: 0.0259

Gnomad4 SAS exome AF: 0.0154

Gnomad4 FIN exome AF: 0.00199

Gnomad4 NFE exome AF: 0.0168

Gnomad4 OTH exome AF: 0.0156

GnomAD4 genome AF: 0.00565 AC: 246 AN: 43554 Hom.: 8 Cov.: 3 AF XY: 0.00568 AC XY: 119 AN XY: 20968

Gnomad4 AFR AF: 0.00182

Gnomad4 AMR AF: 0.00274

Gnomad4 ASJ AF: 0.00672

Gnomad4 EAS AF: 0.0446

Gnomad4 SAS AF: 0.0297

Gnomad4 FIN AF: 0.00260

Gnomad4 NFE AF: 0.00524

Gnomad4 OTH AF: 0.00189

ExAC AF: 0.0440 AC: 4879

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

HLA-B-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 17, 2020

This variant is classified as likely 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	Uncertain	0.37
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.31
Cadd	Benign	17
Dann	Benign	0.60
DEOGEN2	Benign	0.053	T;.;T
Eigen	Benign	-0.72
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.026	N
LIST_S2	Benign	0.014	T;T;T
MetaRNN	Benign	0.0062	T;T;T
MetaSVM	Benign	-0.98	T
MutationTaster	Benign	1.0	N
PROVEAN	Pathogenic	-5.6	D;.;D
REVEL	Benign	0.16
Sift	Uncertain	0.0020	D;.;D
Sift4G	Uncertain	0.0020	D;.;D
Polyphen		0.99	D;.;.
Vest4		0.16
MutPred		0.47		Loss of disorder (P = 0.03);Loss of disorder (P = 0.03);.;
MPC		0.83
ClinPred		0.14	T
GERP RS		-0.99
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.57
gMVP		0.12

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: rs3180380; hg19: chr6-31324489; COSMIC: COSV69521794; COSMIC: COSV69521794;