rs378352

Positions:

• chr6-33007157-G-A
• chr6-33007157-G-C

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_Moderate BP7 BA1

The NM_002119.4(HLA-DOA):​c.672C>T​(p.Gly224=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.205 in 1,613,678 control chromosomes in the GnomAD database, including 36,516 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 0.17 (2813 hom., cov: 32)
  • Exomes 𝑓: 0.21 (33703 hom.)
• Consequence: HLA-DOA NM_002119.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.302

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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.37).
• BP7: Synonymous conserved (PhyloP=0.302 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.371 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HLA-DOA	NM_002119.4	c.672C>T	p.Gly224=	synonymous_variant	4/5	ENST00000229829.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HLA-DOA	ENST00000229829.7	c.672C>T	p.Gly224=	synonymous_variant	4/5		NM_002119.4	P1
HLA-DOA	ENST00000485901.1	n.478C>T		non_coding_transcript_exon_variant	2/3
HLA-DOA	ENST00000490305.5	n.90C>T		non_coding_transcript_exon_variant	2/3

Frequencies

GnomAD3 genomes AF: 0.169 AC: 25728 AN: 152092 Hom.: 2809 Cov.: 32

Gnomad AFR AF: 0.0480

Gnomad AMI AF: 0.197

Gnomad AMR AF: 0.150

Gnomad ASJ AF: 0.0966

Gnomad EAS AF: 0.384

Gnomad SAS AF: 0.181

Gnomad FIN AF: 0.245

Gnomad MID AF: 0.114

Gnomad NFE AF: 0.223

Gnomad OTH AF: 0.142

GnomAD3 exomes AF: 0.204 AC: 51025 AN: 250536 Hom.: 6238 AF XY: 0.207 AC XY: 28158 AN XY: 135740

Gnomad AFR exome AF: 0.0422

Gnomad AMR exome AF: 0.124

Gnomad ASJ exome AF: 0.0905

Gnomad EAS exome AF: 0.415

Gnomad SAS exome AF: 0.174

Gnomad FIN exome AF: 0.248

Gnomad NFE exome AF: 0.227

Gnomad OTH exome AF: 0.188

GnomAD4 exome AF: 0.209 AC: 305752 AN: 1461468 Hom.: 33703 Cov.: 45 AF XY: 0.210 AC XY: 152355 AN XY: 727062

Gnomad4 AFR exome AF: 0.0392

Gnomad4 AMR exome AF: 0.126

Gnomad4 ASJ exome AF: 0.0942

Gnomad4 EAS exome AF: 0.324

Gnomad4 SAS exome AF: 0.175

Gnomad4 FIN exome AF: 0.249

Gnomad4 NFE exome AF: 0.218

Gnomad4 OTH exome AF: 0.198

GnomAD4 genome AF: 0.169 AC: 25735 AN: 152210 Hom.: 2813 Cov.: 32 AF XY: 0.172 AC XY: 12800 AN XY: 74420

Gnomad4 AFR AF: 0.0479

Gnomad4 AMR AF: 0.150

Gnomad4 ASJ AF: 0.0966

Gnomad4 EAS AF: 0.385

Gnomad4 SAS AF: 0.180

Gnomad4 FIN AF: 0.245

Gnomad4 NFE AF: 0.223

Gnomad4 OTH AF: 0.146

Alfa AF: 0.197 Hom.: 3695

Bravo AF: 0.155

Asia WGS AF: 0.217 AC: 755 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
CADD	Benign	7.0
DANN	Benign	0.75

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: rs378352; hg19: chr6-32974934; COSMIC: COSV57713771; COSMIC: COSV57713771;