6-31356732-T-G

Variant names:

• chr6-31356732-T-G
• rs41553715
• NM_005514.8:c.299A>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

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. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. E100V) has been classified as Uncertain significance.

• 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
• Publications: 21 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]

ENSG00000271581 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.093381345).

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.299A>C	p.Glu100Ala	missense	Exon 2 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.299A>C	p.Glu100Ala	missense	Exon 2 of 8	ENSP00000399168.2
	HLA-B	ENST00000696559.1		c.299A>C	p.Glu100Ala	missense	Exon 5 of 11	ENSP00000512717.1
	HLA-B	ENST00000696560.1		c.299A>C	p.Glu100Ala	missense	Exon 4 of 10	ENSP00000512718.1

Frequencies

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

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

⚠️ 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: 19760

American (AMR) AF: 0.00 AC: 0 AN: 31056

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18440

East Asian (EAS) AF: 0.00 AC: 0 AN: 23586

South Asian (SAS) AF: 0.0000181 AC: 1 AN: 55270

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33440

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3078

European-Non Finnish (NFE) AF: 0.00000501 AC: 4 AN: 797758

Other (OTH) AF: 0.00 AC: 0 AN: 41314

⚠️ 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 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

African (AFR) AF: 0.00 AC: 0 AN: 14936

American (AMR) AF: 0.00 AC: 0 AN: 5100

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1576

East Asian (EAS) AF: 0.00 AC: 0 AN: 1556

South Asian (SAS) AF: 0.00 AC: 0 AN: 940

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 4164

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 82

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 28114

Other (OTH) AF: 0.00 AC: 0 AN: 698

Alfa AF: 0.00 Hom.: 11

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.010	N
LIST_S2	Benign	0.047	T
M_CAP	Benign	0.0031	T
MetaRNN	Benign	0.093	T
MetaSVM	Benign	-0.98	T
PhyloP100		-4.3
PROVEAN	Benign	0.89	N
REVEL	Benign	0.15
Sift	Benign	0.068	T
Sift4G	Benign	0.22	T
Polyphen		0.053	B
Vest4		0.054
MutPred		0.36		Gain of MoRF binding (P = 0.0376)
MVP		0.030
MPC		0.28
ClinPred		0.10	T
GERP RS		-3.1
PromoterAI		0.026	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.23
gMVP		0.13
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs41553715; hg19: chr6-31324509;