6-31356732-T-G

Position:

• chr6-31356732-T-G

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BS2_Supporting

The NM_005514.8(HLA-B):​c.299A>C​(p.Glu100Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000488 in 1,023,702 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. E100V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 7)
  • Exomes 𝑓: 0.0000049 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: HLA-B NM_005514.8 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -4.33

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]

ENSG00000271581 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.093381345).
• BS2: High AC in GnomAdExome4 at 5 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HLA-B	NM_005514.8	c.299A>C	p.Glu100Ala	missense_variant	2/8	ENST00000412585.7	NP_005505.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HLA-B	ENST00000412585.7	c.299A>C	p.Glu100Ala	missense_variant	2/8	6	NM_005514.8	ENSP00000399168.2

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 57494 Hom.: 0 Cov.: 7 FAILED QC

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 AF: 0.00000488 AC: 5 AN: 1023702 Hom.: 0 Cov.: 24 AF XY: 0.00000197 AC XY: 1 AN XY: 507908

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000181

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000501

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 57494 Hom.: 0 Cov.: 7 AF XY: 0.00 AC XY: 0 AN XY: 27576

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	3.8
DANN	Benign	0.36
DEOGEN2	Benign	0.016	T;.;T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.010	N
LIST_S2	Benign	0.047	T;T;T
M_CAP	Benign	0.0031	T
MetaRNN	Benign	0.093	T;T;T
MetaSVM	Benign	-0.98	T
PROVEAN	Benign	0.89	N;.;N
REVEL	Benign	0.15
Sift	Benign	0.068	T;.;D
Sift4G	Benign	0.22	T;.;T
Polyphen		0.053	B;.;.
Vest4		0.054
MutPred		0.36		Gain of MoRF binding (P = 0.0376);Gain of MoRF binding (P = 0.0376);.;
MVP		0.030
MPC		0.28
ClinPred		0.10	T
GERP RS		-3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.23
gMVP		0.13

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs41553715; hg19: chr6-31324509;