rs1071652

Variant names:

• chr6-31356424-C-A
• rs1071652
• NM_005514.8:c.362G>T

Your query was ambiguous. Multiple possible variants found:

• chr6-31356424-C-A
• chr6-31356424-C-G
• chr6-31356424-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_005514.8(HLA-B):​c.362G>T​(p.Ser121Ile) 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. 12/21 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. S121R) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.00042 (0 hom., cov: 4)
  • Exomes 𝑓: 0.0032 (26 hom.)
• Consequence: HLA-B NM_005514.8 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.73
• Publications: 27 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]

ENSG00000298426 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HLA-B	NM_005514.8	c.362G>T	p.Ser121Ile	missense_variant	Exon 3 of 8	ENST00000412585.7	NP_005505.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HLA-B	ENST00000412585.7	c.362G>T	p.Ser121Ile	missense_variant	Exon 3 of 8	6	NM_005514.8	ENSP00000399168.2

Frequencies

GnomAD3 genomes AF: 0.000425 AC: 19 AN: 44734 Hom.: 0 Cov.: 4

Gnomad AFR AF: 0.00104

Gnomad AMI AF: 0.00495

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000215

Gnomad OTH AF: 0.00219

GnomAD2 exomes AF: 0.0198 AC: 3623 AN: 182648 AF XY: 0.0203

Gnomad AFR exome AF: 0.0446

Gnomad AMR exome AF: 0.0110

Gnomad ASJ exome AF: 0.0363

Gnomad EAS exome AF: 0.00165

Gnomad FIN exome AF: 0.00643

Gnomad NFE exome AF: 0.0189

Gnomad OTH exome AF: 0.0233

GnomAD4 exome AF: 0.00320 AC: 2789 AN: 871158 Hom.: 26 Cov.: 14 AF XY: 0.00352 AC XY: 1522 AN XY: 432650

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

African (AFR) AF: 0.00571 AC: 108 AN: 18914

American (AMR) AF: 0.00347 AC: 91 AN: 26224

Ashkenazi Jewish (ASJ) AF: 0.00936 AC: 95 AN: 10146

East Asian (EAS) AF: 0.000428 AC: 10 AN: 23366

South Asian (SAS) AF: 0.00952 AC: 483 AN: 50744

European-Finnish (FIN) AF: 0.000824 AC: 21 AN: 25494

Middle Eastern (MID) AF: 0.00177 AC: 3 AN: 1694

European-Non Finnish (NFE) AF: 0.00269 AC: 1831 AN: 681044

Other (OTH) AF: 0.00438 AC: 147 AN: 33532

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000425 AC: 19 AN: 44752 Hom.: 0 Cov.: 4 AF XY: 0.000426 AC XY: 9 AN XY: 21134

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

African (AFR) AF: 0.00104 AC: 12 AN: 11552

American (AMR) AF: 0.00 AC: 0 AN: 3468

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 410

East Asian (EAS) AF: 0.00 AC: 0 AN: 1486

South Asian (SAS) AF: 0.00 AC: 0 AN: 570

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 3262

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 30

European-Non Finnish (NFE) AF: 0.000215 AC: 5 AN: 23308

Other (OTH) AF: 0.00216 AC: 1 AN: 464

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0150 Hom.: 47

ExAC AF: 0.0288 AC: 3246

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	12
DANN	Benign	0.84
DEOGEN2	Benign	0.022	T;.;T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.048	N
LIST_S2	Benign	0.0037	T;T;T
MetaRNN	Benign	0.0053	T;T;T
MetaSVM	Benign	-0.87	T
PhyloP100		-2.7
PROVEAN	Benign	-1.2	N;.;N
REVEL	Benign	0.24
Sift	Benign	0.17	T;.;D
Sift4G	Benign	0.26	T;.;T
Polyphen		0.78	P;.;.
Vest4		0.049
MPC		0.73
ClinPred		0.021	T
GERP RS		-6.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.23
gMVP		0.18
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.32		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.32		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1071652; hg19: chr6-31324201;