6-31356825-T-G

Variant names:

• chr6-31356825-T-G
• rs41562914
• NM_005514.8:c.206A>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_005514.8(HLA-B):​c.206A>C​(p.Glu69Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000288 in 1,039,864 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.

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0000029 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: HLA-B NM_005514.8 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -4.91
• Publications: 23 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.003656).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HLA-B	NM_005514.8	c.206A>C	p.Glu69Ala	missense_variant	Exon 2 of 8	ENST00000412585.7	NP_005505.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HLA-B	ENST00000412585.7	c.206A>C	p.Glu69Ala	missense_variant	Exon 2 of 8	6	NM_005514.8	ENSP00000399168.2

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 37850 Hom.: 0 Cov.: 0

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

GnomAD2 exomes AF: 0.0000148 AC: 2 AN: 135230 AF XY: 0.0000138

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000494

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000288 AC: 3 AN: 1039864 Hom.: 0 Cov.: 27 AF XY: 0.00000387 AC XY: 2 AN XY: 517144

⚠️ 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: 22014

American (AMR) AF: 0.00 AC: 0 AN: 32046

Ashkenazi Jewish (ASJ) AF: 0.0000489 AC: 1 AN: 20440

East Asian (EAS) AF: 0.00 AC: 0 AN: 25126

South Asian (SAS) AF: 0.00 AC: 0 AN: 57054

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34826

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2938

European-Non Finnish (NFE) AF: 0.00000249 AC: 2 AN: 802520

Other (OTH) AF: 0.00 AC: 0 AN: 42900

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00380082), 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: 37850 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 17428

African (AFR) AF: 0.00 AC: 0 AN: 8320

American (AMR) AF: 0.00 AC: 0 AN: 3160

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1006

East Asian (EAS) AF: 0.00 AC: 0 AN: 816

South Asian (SAS) AF: 0.00 AC: 0 AN: 484

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2424

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 52

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 21010

Other (OTH) AF: 0.00 AC: 0 AN: 386

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.000385 AC: 35

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	3.9
DANN	Benign	0.36
DEOGEN2	Benign	0.017	T
Eigen	Benign	-1.9
Eigen_PC	Benign	-2.1
FATHMM_MKL	Benign	0.0057	N
LIST_S2	Benign	0.0026	T
MetaRNN	Benign	0.0037	T
MetaSVM	Benign	-0.99	T
PhyloP100		-4.9
PROVEAN	Benign	0.18	N
REVEL	Benign	0.16
Sift	Benign	0.078	T
Sift4G	Benign	0.22	T
Polyphen		0.0010	B
Vest4		0.10
MVP		0.030
MPC		0.25
ClinPred		0.035	T
GERP RS		-6.4
PromoterAI		-0.031	Neutral
Varity_R		0.31
gMVP		0.13
Mutation Taster		=100/0	polymorphism (auto)

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: rs41562914; hg19: chr6-31324602; COSMIC: COSV69520465; COSMIC: COSV69520465;