6-31356367-T-G

Variant names:

• chr6-31356367-T-G
• rs4997052
• NM_005514.8:c.419A>C

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_005514.8(HLA-B):​c.419A>C​(p.Tyr140Ser) 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. Variant has been reported in ClinVar as Benign (no stars).

• 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 no assertion criteria provided B:1
• Conservation: PhyloP100: -8.15
• Publications: 34 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]

ENSG00000298396 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -5 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 VariationId is 3060941.Status of the report is no_assertion_criteria_provided, 0 stars.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HLA-B	NM_005514.8	MANE Select	c.419A>C	p.Tyr140Ser	missense	Exon 3 of 8	NP_005505.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HLA-B	ENST00000412585.7	TSL:6 MANE Select	c.419A>C	p.Tyr140Ser	missense	Exon 3 of 8	ENSP00000399168.2
	HLA-B	ENST00000696559.1		c.419A>C	p.Tyr140Ser	missense	Exon 6 of 11	ENSP00000512717.1
	HLA-B	ENST00000696560.1		c.419A>C	p.Tyr140Ser	missense	Exon 5 of 10	ENSP00000512718.1

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

GnomAD2 exomes AF: 0.215 AC: 40300 AN: 187878 AF XY: 0.212

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 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

African (AFR) AF: 0.279 AC: 5279 AN: 18938

American (AMR) AF: 0.161 AC: 4338 AN: 26910

Ashkenazi Jewish (ASJ) AF: 0.202 AC: 2471 AN: 12250

East Asian (EAS) AF: 0.104 AC: 2597 AN: 25080

South Asian (SAS) AF: 0.184 AC: 10486 AN: 56958

European-Finnish (FIN) AF: 0.0758 AC: 2108 AN: 27820

Middle Eastern (MID) AF: 0.220 AC: 488 AN: 2222

European-Non Finnish (NFE) AF: 0.159 AC: 103123 AN: 646608

Other (OTH) AF: 0.157 AC: 5354 AN: 34054

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

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

African (AFR) AF: 0.0238 AC: 191 AN: 8032

American (AMR) AF: 0.0525 AC: 160 AN: 3046

Ashkenazi Jewish (ASJ) AF: 0.0160 AC: 6 AN: 374

East Asian (EAS) AF: 0.0508 AC: 64 AN: 1260

South Asian (SAS) AF: 0.0124 AC: 9 AN: 726

European-Finnish (FIN) AF: 0.0141 AC: 36 AN: 2560

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 38

European-Non Finnish (NFE) AF: 0.0110 AC: 213 AN: 19430

Other (OTH) AF: 0.0241 AC: 9 AN: 374

⚠️ 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: 0.149 Hom.: 295

ESP6500AA AF: 0.250 AC: 1047

ESP6500EA AF: 0.185 AC: 1548

ExAC AF: 0.184 AC: 21829

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	HLA-B-related disorder (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-3.2
Eigen_PC	Benign	-3.3
FATHMM_MKL	Benign	0.0075	N
LIST_S2	Benign	0.0056	T
MetaRNN	Benign	0.0088	T
MetaSVM	Benign	-0.97	T
PhyloP100		-8.1
PROVEAN	Uncertain	-2.8	D
REVEL	Uncertain	0.32
Sift	Benign	0.49	T
Sift4G	Benign	0.36	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
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4997052; hg19: chr6-31324144; COSMIC: COSV69520601; COSMIC: COSV69520601;