NM_005514.8:c.175A>G

Variant names:

• chr6-31356856-T-C
• rs1065378
• NM_005514.8:c.175A>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_005514.8(HLA-B):​c.175A>G​(p.Arg59Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000918 in 1,089,908 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 9)
  • Exomes 𝑓: 9.2e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: HLA-B NM_005514.8 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.221
• Publications: 5 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.37735406).

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.175A>G	p.Arg59Gly	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.175A>G	p.Arg59Gly	missense	Exon 2 of 8	ENSP00000399168.2	P01889
	HLA-B	ENST00000696559.1		c.175A>G	p.Arg59Gly	missense	Exon 5 of 11	ENSP00000512717.1	P01889
	HLA-B	ENST00000696560.1		c.175A>G	p.Arg59Gly	missense	Exon 4 of 10	ENSP00000512718.1	P01889

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 67994 Hom.: 0 Cov.: 9

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: 0.00 AC: 0 AN: 226310 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 9.18e-7 AC: 1 AN: 1089908 Hom.: 0 Cov.: 27 AF XY: 0.00000184 AC XY: 1 AN XY: 542272

⚠️ 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: 23304

American (AMR) AF: 0.00 AC: 0 AN: 33342

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21402

East Asian (EAS) AF: 0.00 AC: 0 AN: 26588

South Asian (SAS) AF: 0.00 AC: 0 AN: 58780

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35856

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3096

European-Non Finnish (NFE) AF: 0.00000119 AC: 1 AN: 842474

Other (OTH) AF: 0.00 AC: 0 AN: 45066

⚠️ 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 AF: 0.00 AC: 0 AN: 67994 Hom.: 0 Cov.: 9 AF XY: 0.00 AC XY: 0 AN XY: 32126

African (AFR) AF: 0.00 AC: 0 AN: 17146

American (AMR) AF: 0.00 AC: 0 AN: 6384

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2054

East Asian (EAS) AF: 0.00 AC: 0 AN: 1568

South Asian (SAS) AF: 0.00 AC: 0 AN: 1274

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 4700

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 152

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 33530

Other (OTH) AF: 0.00 AC: 0 AN: 798

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Uncertain	0.044	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	23
DANN	Benign	0.95
DEOGEN2	Benign	0.019	T
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.81
FATHMM_MKL	Benign	0.026	N
LIST_S2	Benign	0.20	T
M_CAP	Benign	0.0092	T
MetaRNN	Benign	0.38	T
MetaSVM	Benign	-0.95	T
PhyloP100		-0.22
PROVEAN	Pathogenic	-5.4	D
REVEL	Benign	0.19
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.040	D
Polyphen		0.62	P
Vest4		0.33
MutPred		0.64		Gain of catalytic residue at F60 (P = 0.0488)
MVP		0.17
MPC		0.48
ClinPred		0.73	D
GERP RS		1.2
PromoterAI		-0.036	Neutral
Varity_R		0.78
gMVP		0.34
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1065378; hg19: chr6-31324633;