6-31356424-C-T

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_005514.8(HLA-B):​c.362G>A​(p.Ser121Asn) 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. 13/19 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 0.00081 (0 hom., cov: 4)
  • Exomes 𝑓: 0.014 (94 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0048499107).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HLA-B	NM_005514.8	c.362G>A	p.Ser121Asn	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>A	p.Ser121Asn	missense_variant	Exon 3 of 8	6	NM_005514.8	ENSP00000399168.2

Frequencies

GnomAD3 genomes AF: 0.000805 AC: 36 AN: 44696 Hom.: 0 Cov.: 4

Gnomad AFR AF: 0.000433

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000579

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000671

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00123

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00103

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0313 AC: 5711 AN: 182648 AF XY: 0.0318

Gnomad AFR exome AF: 0.00943

Gnomad AMR exome AF: 0.0172

Gnomad ASJ exome AF: 0.0194

Gnomad EAS exome AF: 0.0319

Gnomad FIN exome AF: 0.0667

Gnomad NFE exome AF: 0.0360

Gnomad OTH exome AF: 0.0390

GnomAD4 exome AF: 0.0139 AC: 11971 AN: 861596 Hom.: 94 Cov.: 14 AF XY: 0.0140 AC XY: 6001 AN XY: 427896

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

African (AFR) AF: 0.00432 AC: 82 AN: 18994

American (AMR) AF: 0.0110 AC: 287 AN: 26046

Ashkenazi Jewish (ASJ) AF: 0.0140 AC: 143 AN: 10192

East Asian (EAS) AF: 0.00860 AC: 200 AN: 23248

South Asian (SAS) AF: 0.00916 AC: 467 AN: 51002

European-Finnish (FIN) AF: 0.0208 AC: 520 AN: 24960

Middle Eastern (MID) AF: 0.0124 AC: 21 AN: 1688

European-Non Finnish (NFE) AF: 0.0145 AC: 9773 AN: 672242

Other (OTH) AF: 0.0144 AC: 478 AN: 33224

⚠️ 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: 0.000805 AC: 36 AN: 44714 Hom.: 0 Cov.: 4 AF XY: 0.000947 AC XY: 20 AN XY: 21124

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

African (AFR) AF: 0.000432 AC: 5 AN: 11574

American (AMR) AF: 0.000578 AC: 2 AN: 3460

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 412

East Asian (EAS) AF: 0.000676 AC: 1 AN: 1480

South Asian (SAS) AF: 0.00 AC: 0 AN: 574

European-Finnish (FIN) AF: 0.00123 AC: 4 AN: 3242

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

European-Non Finnish (NFE) AF: 0.00103 AC: 24 AN: 23272

Other (OTH) AF: 0.00 AC: 0 AN: 466

⚠️ 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: 0.0897 Hom.: 47

ESP6500AA AF: 0.00110 AC: 4

ESP6500EA AF: 0.00620 AC: 49

ExAC AF: 0.0356 AC: 4023

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	4.0
DANN	Benign	0.78
DEOGEN2	Benign	0.018	T;.;T
Eigen	Benign	-1.9
Eigen_PC	Benign	-2.0
FATHMM_MKL	Benign	0.026	N
LIST_S2	Benign	0.0034	T;T;T
MetaRNN	Benign	0.0048	T;T;T
MetaSVM	Benign	-0.92	T
PhyloP100		-2.7
PROVEAN	Benign	-0.29	N;.;N
REVEL	Benign	0.063
Sift	Benign	0.19	T;.;T
Sift4G	Benign	0.52	T;.;T
Polyphen		0.0	B;.;.
Vest4		0.045
MPC		0.22
ClinPred		0.0028	T
GERP RS		-6.4
Varity_R		0.14
gMVP		0.097
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs1071652; hg19: chr6-31324201;