6-31356418-T-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_005514.8(HLA-B):c.368A>T(p.Tyr123Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y123S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00036 (0 hom., cov: 5)
  • Exomes 𝑓: 0.014 (580 hom.)
  • Failed GnomAD Quality Control
• Consequence: HLA-B NM_005514.8 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.869

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]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.013129115).
• BP6: Variant 6-31356418-T-A is Benign according to our data. Variant chr6-31356418-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 2656394.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd at 17 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HLA-B	NM_005514.8	c.368A>T	p.Tyr123Phe	missense_variant	3/8	ENST00000412585.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HLA-B	ENST00000412585.7	c.368A>T	p.Tyr123Phe	missense_variant	3/8		NM_005514.8	P1

Frequencies

GnomAD3 genomes AF: 0.000365 AC: 17 AN: 46622 Hom.: 0 Cov.: 5

Gnomad AFR AF: 0.00102

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000283

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000599

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000811

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00489 AC: 983 AN: 200890 Hom.: 39 AF XY: 0.00467 AC XY: 512 AN XY: 109542

Gnomad AFR exome AF: 0.0104

Gnomad AMR exome AF: 0.00576

Gnomad ASJ exome AF: 0.00392

Gnomad EAS exome AF: 0.00682

Gnomad SAS exome AF: 0.00413

Gnomad FIN exome AF: 0.00798

Gnomad NFE exome AF: 0.00329

Gnomad OTH exome AF: 0.00523

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0145 AC: 12468 AN: 862604 Hom.: 580 Cov.: 14 AF XY: 0.0147 AC XY: 6288 AN XY: 428770

Gnomad4 AFR exome AF: 0.0437

Gnomad4 AMR exome AF: 0.0550

Gnomad4 ASJ exome AF: 0.0485

Gnomad4 EAS exome AF: 0.00270

Gnomad4 SAS exome AF: 0.0255

Gnomad4 FIN exome AF: 0.00975

Gnomad4 NFE exome AF: 0.0114

Gnomad4 OTH exome AF: 0.0144

GnomAD4 genome AF: 0.000364 AC: 17 AN: 46642 Hom.: 0 Cov.: 5 AF XY: 0.000454 AC XY: 10 AN XY: 22040

Gnomad4 AFR AF: 0.00102

Gnomad4 AMR AF: 0.000282

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000599

Gnomad4 NFE AF: 0.0000811

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00733 Hom.: 11

ExAC AF: 0.00507 AC: 576

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jul 01, 2023

HLA-B: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.54
Cadd	Benign	5.5
Dann	Benign	0.41
DEOGEN2	Benign	0.030	T;.;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.077	N
LIST_S2	Benign	0.026	T;T;T
M_CAP	Benign	0.0017	T
MetaRNN	Benign	0.013	T;T;T
MetaSVM	Benign	-0.90	T
MutationTaster	Benign	1.0	N
PROVEAN	Uncertain	-2.6	D;.;N
REVEL	Benign	0.085
Sift	Uncertain	0.021	D;.;D
Sift4G	Benign	0.19	T;.;T
Polyphen		0.0010	B;.;.
Vest4		0.16
MVP		0.095
MPC		0.21
ClinPred		0.0074	T
GERP RS		-3.4
Varity_R		0.44
gMVP		0.062

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs151341218; hg19: chr6-31324195; COSMIC: COSV69521115; COSMIC: COSV69521115;