6-31356423-G-A

Variant names:

• chr6-31356423-G-A
• rs1140412
• NM_005514.8:c.363C>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP7

The NM_005514.8(HLA-B):​c.363C>T​(p.Ser121Ser) variant causes a synonymous 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. Variant has been reported in ClinVar as (no stars).

• Frequency:
  • Genomes: 𝑓 0.00099 (0 hom., cov: 3)
  • Exomes 𝑓: 0.015 (95 hom.)
  • Failed GnomAD Quality Control
• Consequence: HLA-B NM_005514.8 synonymous
• 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 -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP7: Synonymous conserved (PhyloP=-1.84 with no splicing effect.

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>T	p.Ser121Ser	synonymous	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>T	p.Ser121Ser	synonymous	Exon 3 of 8	ENSP00000399168.2	P01889
	HLA-B	ENST00000696559.1		c.363C>T	p.Ser121Ser	synonymous	Exon 6 of 11	ENSP00000512717.1	P01889
	HLA-B	ENST00000696560.1		c.363C>T	p.Ser121Ser	synonymous	Exon 5 of 10	ENSP00000512718.1	P01889

Frequencies

GnomAD3 genomes AF: 0.000995 AC: 36 AN: 36186 Hom.: 0 Cov.: 3

Gnomad AFR AF: 0.000465

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000735

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000763

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00154

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00128

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0318 AC: 5650 AN: 177552 AF XY: 0.0321

Gnomad AFR exome AF: 0.0101

Gnomad AMR exome AF: 0.0178

Gnomad ASJ exome AF: 0.0192

Gnomad EAS exome AF: 0.0301

Gnomad FIN exome AF: 0.0681

Gnomad NFE exome AF: 0.0371

Gnomad OTH exome AF: 0.0392

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0151 AC: 11906 AN: 787924 Hom.: 95 Cov.: 14 AF XY: 0.0152 AC XY: 5966 AN XY: 393120

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

African (AFR) AF: 0.00480 AC: 85 AN: 17708

American (AMR) AF: 0.0117 AC: 285 AN: 24456

Ashkenazi Jewish (ASJ) AF: 0.0150 AC: 145 AN: 9658

East Asian (EAS) AF: 0.00921 AC: 214 AN: 23244

South Asian (SAS) AF: 0.00982 AC: 489 AN: 49812

European-Finnish (FIN) AF: 0.0216 AC: 500 AN: 23164

Middle Eastern (MID) AF: 0.0139 AC: 22 AN: 1588

European-Non Finnish (NFE) AF: 0.0160 AC: 9695 AN: 607544

Other (OTH) AF: 0.0153 AC: 471 AN: 30750

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000995 AC: 36 AN: 36194 Hom.: 0 Cov.: 3 AF XY: 0.00113 AC XY: 19 AN XY: 16814

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

African (AFR) AF: 0.000464 AC: 4 AN: 8612

American (AMR) AF: 0.000734 AC: 2 AN: 2726

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

East Asian (EAS) AF: 0.000769 AC: 1 AN: 1300

South Asian (SAS) AF: 0.00 AC: 0 AN: 494

European-Finnish (FIN) AF: 0.00154 AC: 4 AN: 2594

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

European-Non Finnish (NFE) AF: 0.00128 AC: 25 AN: 19598

Other (OTH) AF: 0.00 AC: 0 AN: 352

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0383 Hom.: 3333

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	7.1
DANN	Benign	0.80
PhyloP100		-1.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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;