6-31356367-T-G

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.419A>C(p.Tyr140Ser) 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 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. Y140D) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.019 (82 hom., cov: 3)
  • Exomes 𝑓: 0.16 (16503 hom.)
  • Failed GnomAD Quality Control
• Consequence: HLA-B NM_005514.8 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -8.15

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=0.008836359).
• BP6: Variant 6-31356367-T-G is Benign according to our data. Variant chr6-31356367-T-G is described in ClinVar as [Benign]. Clinvar id is 3060941.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0192 (690/35974) while in subpopulation AMR AF= 0.0525 (160/3046). AF 95% confidence interval is 0.0459. There are 82 homozygotes in gnomad4. There are 340 alleles in male gnomad4 subpopulation. Median coverage is 3. This position pass quality control queck.
• BS2: High AC in GnomAd at 685 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HLA-B	NM_005514.8	c.419A>C	p.Tyr140Ser	missense_variant	3/8	ENST00000412585.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HLA-B	ENST00000412585.7	c.419A>C	p.Tyr140Ser	missense_variant	3/8		NM_005514.8	P1

Frequencies

GnomAD3 genomes AF: 0.0190 AC: 685 AN: 35964 Hom.: 79 Cov.: 3

Gnomad AFR AF: 0.0239

Gnomad AMI AF: 0.0149

Gnomad AMR AF: 0.0501

Gnomad ASJ AF: 0.0160

Gnomad EAS AF: 0.0521

Gnomad SAS AF: 0.0123

Gnomad FIN AF: 0.0141

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0110

Gnomad OTH AF: 0.0247

GnomAD3 exomes AF: 0.215 AC: 40300 AN: 187878 Hom.: 3187 AF XY: 0.212 AC XY: 21755 AN XY: 102434

Gnomad AFR exome AF: 0.298

Gnomad AMR exome AF: 0.197

Gnomad ASJ exome AF: 0.152

Gnomad EAS exome AF: 0.323

Gnomad SAS exome AF: 0.212

Gnomad FIN exome AF: 0.235

Gnomad NFE exome AF: 0.194

Gnomad OTH exome AF: 0.213

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.160 AC: 136244 AN: 850840 Hom.: 16503 Cov.: 17 AF XY: 0.160 AC XY: 68396 AN XY: 427478

Gnomad4 AFR exome AF: 0.279

Gnomad4 AMR exome AF: 0.161

Gnomad4 ASJ exome AF: 0.202

Gnomad4 EAS exome AF: 0.104

Gnomad4 SAS exome AF: 0.184

Gnomad4 FIN exome AF: 0.0758

Gnomad4 NFE exome AF: 0.159

Gnomad4 OTH exome AF: 0.157

GnomAD4 genome AF: 0.0192 AC: 690 AN: 35974 Hom.: 82 Cov.: 3 AF XY: 0.0200 AC XY: 340 AN XY: 17018

Gnomad4 AFR AF: 0.0238

Gnomad4 AMR AF: 0.0525

Gnomad4 ASJ AF: 0.0160

Gnomad4 EAS AF: 0.0508

Gnomad4 SAS AF: 0.0124

Gnomad4 FIN AF: 0.0141

Gnomad4 NFE AF: 0.0110

Gnomad4 OTH AF: 0.0241

Alfa AF: 0.149 Hom.: 295

ESP6500AA AF: 0.250 AC: 1047

ESP6500EA AF: 0.185 AC: 1548

ExAC AF: 0.184 AC: 21829

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	0.24
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.43
Cadd	Benign	0.0050
Dann	Benign	0.30
DEOGEN2	Benign	0.017	T;.;T
Eigen	Benign	-3.2
Eigen_PC	Benign	-3.3
FATHMM_MKL	Benign	0.0075	N
LIST_S2	Benign	0.0056	T;T;T
MetaRNN	Benign	0.0088	T;T;T
MetaSVM	Benign	-0.97	T
MutationTaster	Benign	1.0	P
PROVEAN	Uncertain	-2.8	D;.;N
REVEL	Uncertain	0.32
Sift	Benign	0.49	T;.;T
Sift4G	Benign	0.36	T;.;T
Polyphen		0.0	B;.;.
Vest4		0.053
MPC		0.36
ClinPred		0.018	T
GERP RS		-6.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.48
gMVP		0.28

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs4997052; hg19: chr6-31324144; COSMIC: COSV69520601; COSMIC: COSV69520601;