rs375256

chr6-33008092-G-Achr6-33008092-G-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_002119.4(HLA-DOA):c.252C>T(p.Gly84=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.236 in 1,612,792 control chromosomes in the GnomAD database, including 47,458 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.20 (3711 hom., cov: 33)
  • Exomes 𝑓: 0.24 (43747 hom.)
• Consequence: HLA-DOA NM_002119.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.92

Genes affected

HLA-DOA (HGNC:4936): (major histocompatibility complex, class II, DO alpha) HLA-DOA belongs to the HLA class II alpha chain paralogues. HLA-DOA forms a heterodimer with HLA-DOB. The heterodimer, HLA-DO, is found in lysosomes in B cells and regulates HLA-DM-mediated peptide loading on MHC class II molecules. In comparison with classical HLA class II molecules, this gene exhibits very little sequence variation, especially at the protein level. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0011001527).
• BP7: Synonymous conserved (PhyloP=-3.92 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.373 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HLA-DOA	NM_002119.4	c.252C>T	p.Gly84=	synonymous_variant	2/5	ENST00000229829.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HLA-DOA	ENST00000229829.7	c.252C>T	p.Gly84=	synonymous_variant	2/5		NM_002119.4	P1

Frequencies

GnomAD3 genomes AF: 0.204 AC: 31031 AN: 152052 Hom.: 3704 Cov.: 33

Gnomad AFR AF: 0.0997

Gnomad AMI AF: 0.259

Gnomad AMR AF: 0.170

Gnomad ASJ AF: 0.106

Gnomad EAS AF: 0.386

Gnomad SAS AF: 0.188

Gnomad FIN AF: 0.280

Gnomad MID AF: 0.123

Gnomad NFE AF: 0.256

Gnomad OTH AF: 0.171

GnomAD3 exomes AF: 0.229 AC: 56426 AN: 246120 Hom.: 7459 AF XY: 0.233 AC XY: 31241 AN XY: 134208

Gnomad AFR exome AF: 0.0950

Gnomad AMR exome AF: 0.136

Gnomad ASJ exome AF: 0.0995

Gnomad EAS exome AF: 0.417

Gnomad SAS exome AF: 0.183

Gnomad FIN exome AF: 0.279

Gnomad NFE exome AF: 0.261

Gnomad OTH exome AF: 0.214

GnomAD4 exome AF: 0.240 AC: 350241 AN: 1460622 Hom.: 43747 Cov.: 36 AF XY: 0.239 AC XY: 173799 AN XY: 726624

Gnomad4 AFR exome AF: 0.0973

Gnomad4 AMR exome AF: 0.139

Gnomad4 ASJ exome AF: 0.103

Gnomad4 EAS exome AF: 0.325

Gnomad4 SAS exome AF: 0.183

Gnomad4 FIN exome AF: 0.280

Gnomad4 NFE exome AF: 0.252

Gnomad4 OTH exome AF: 0.224

GnomAD4 genome AF: 0.204 AC: 31063 AN: 152170 Hom.: 3711 Cov.: 33 AF XY: 0.206 AC XY: 15311 AN XY: 74396

Gnomad4 AFR AF: 0.100

Gnomad4 AMR AF: 0.170

Gnomad4 ASJ AF: 0.106

Gnomad4 EAS AF: 0.387

Gnomad4 SAS AF: 0.187

Gnomad4 FIN AF: 0.280

Gnomad4 NFE AF: 0.256

Gnomad4 OTH AF: 0.175

Alfa AF: 0.209 Hom.: 2179

Bravo AF: 0.192

TwinsUK AF: 0.252 AC: 934

ALSPAC AF: 0.245 AC: 943

ESP6500AA AF: 0.101 AC: 306

ESP6500EA AF: 0.255 AC: 1384

ExAC AF: 0.234 AC: 27538

Asia WGS AF: 0.229 AC: 797 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.87	T
BayesDel_noAF	Benign	-0.87
Cadd	Benign	0.20
Dann	Benign	0.62
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.0082	N
MetaRNN	Benign	0.0011	T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.83	P;P
PROVEAN	Benign	0.17	N
REVEL	Benign	0.013
Sift	Benign	0.047	D
ClinPred		0.020	T
GERP RS		-9.0

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

Publications

LitVar

Other links and lift over

dbSNP: rs375256; hg19: chr6-32975869; COSMIC: COSV57714277; COSMIC: COSV57714277;