chr6-31356423-G-T

Variant names:

• chr6-31356423-G-T
• rs1140412
• NM_005514.8:c.363C>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.363C>A​(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. 14/20 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Benign in ClinVar. Synonymous variant affecting the same amino acid position (i.e. S121S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 3)
  • Exomes 𝑓: 0.0000050 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: HLA-B NM_005514.8 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.84
• Publications: 28 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=0.045919478).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005514.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HLA-B	NM_005514.8	MANE Select	c.363C>A	p.Ser121Arg	missense	Exon 3 of 8	NP_005505.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HLA-B	ENST00000412585.7	TSL:6 MANE Select	c.363C>A	p.Ser121Arg	missense	Exon 3 of 8	ENSP00000399168.2	P01889
	HLA-B	ENST00000696559.1		c.363C>A	p.Ser121Arg	missense	Exon 6 of 11	ENSP00000512717.1	P01889
	HLA-B	ENST00000696560.1		c.363C>A	p.Ser121Arg	missense	Exon 5 of 10	ENSP00000512718.1	P01889

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 36348 Hom.: 0 Cov.: 3

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000501 AC: 4 AN: 798894 Hom.: 0 Cov.: 14 AF XY: 0.00000502 AC XY: 2 AN XY: 398728

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

African (AFR) AF: 0.00 AC: 0 AN: 17788

American (AMR) AF: 0.0000406 AC: 1 AN: 24640

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 9700

East Asian (EAS) AF: 0.00 AC: 0 AN: 23354

South Asian (SAS) AF: 0.0000399 AC: 2 AN: 50082

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 23644

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1598

European-Non Finnish (NFE) AF: 0.00000162 AC: 1 AN: 616934

Other (OTH) AF: 0.00 AC: 0 AN: 31154

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000000000417111), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 36348 Hom.: 0 Cov.: 3 AF XY: 0.00 AC XY: 0 AN XY: 16872

African (AFR) AF: 0.00 AC: 0 AN: 8620

American (AMR) AF: 0.00 AC: 0 AN: 2728

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 330

East Asian (EAS) AF: 0.00 AC: 0 AN: 1316

South Asian (SAS) AF: 0.00 AC: 0 AN: 496

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 26

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 19708

Other (OTH) AF: 0.00 AC: 0 AN: 346

Alfa AF: 0.00 Hom.: 3333

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	1.0
DANN	Benign	0.53
DEOGEN2	Benign	0.016	T
Eigen	Benign	-2.1
Eigen_PC	Benign	-2.1
FATHMM_MKL	Benign	0.035	N
LIST_S2	Benign	0.0043	T
M_CAP	Benign	0.0022	T
MetaRNN	Benign	0.046	T
MetaSVM	Benign	-0.89	T
PhyloP100		-1.8
PROVEAN	Benign	1.1	N
REVEL	Benign	0.27
Sift	Benign	1.0	T
Sift4G	Benign	0.70	T
Polyphen		0.071	B
Vest4		0.062
MutPred		0.083		Gain of phosphorylation at T118 (P = 0.1034)
MVP		0.030
MPC		0.27
ClinPred		0.054	T
GERP RS		-2.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.17
gMVP		0.21
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1140412; hg19: chr6-31324200;