rs365066

Positions:

• chr6-33007480-C-T

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.444G>A​(p.Leu148=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.418 in 1,612,352 control chromosomes in the GnomAD database, including 143,730 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 0.40 (12288 hom., cov: 32)
  • Exomes 𝑓: 0.42 (131442 hom.)
• Consequence: HLA-DOA NM_002119.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0810

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=-0.46).
• BP7: Synonymous conserved (PhyloP=-0.081 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.553 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HLA-DOA	NM_002119.4	c.444G>A	p.Leu148=	synonymous_variant	3/5	ENST00000229829.7	NP_002110.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HLA-DOA	ENST00000229829.7	c.444G>A	p.Leu148=	synonymous_variant	3/5		NM_002119.4	ENSP00000229829	P1
HLA-DOA	ENST00000485901.1	n.155G>A		non_coding_transcript_exon_variant	2/3
HLA-DOA	ENST00000495532.1	n.510G>A		non_coding_transcript_exon_variant	2/2
HLA-DOA	ENST00000374813.1			downstream_gene_variant				ENSP00000363946

Frequencies

GnomAD3 genomes AF: 0.398 AC: 60452 AN: 152020 Hom.: 12277 Cov.: 32

Gnomad AFR AF: 0.346

Gnomad AMI AF: 0.475

Gnomad AMR AF: 0.344

Gnomad ASJ AF: 0.275

Gnomad EAS AF: 0.570

Gnomad SAS AF: 0.380

Gnomad FIN AF: 0.451

Gnomad MID AF: 0.326

Gnomad NFE AF: 0.428

Gnomad OTH AF: 0.364

GnomAD3 exomes AF: 0.397 AC: 97712 AN: 246086 Hom.: 20820 AF XY: 0.403 AC XY: 53978 AN XY: 134092

Gnomad AFR exome AF: 0.338

Gnomad AMR exome AF: 0.255

Gnomad ASJ exome AF: 0.275

Gnomad EAS exome AF: 0.583

Gnomad SAS exome AF: 0.366

Gnomad FIN exome AF: 0.445

Gnomad NFE exome AF: 0.430

Gnomad OTH exome AF: 0.380

GnomAD4 exome AF: 0.420 AC: 613863 AN: 1460214 Hom.: 131442 Cov.: 53 AF XY: 0.420 AC XY: 304758 AN XY: 726414

Gnomad4 AFR exome AF: 0.337

Gnomad4 AMR exome AF: 0.268

Gnomad4 ASJ exome AF: 0.280

Gnomad4 EAS exome AF: 0.469

Gnomad4 SAS exome AF: 0.369

Gnomad4 FIN exome AF: 0.447

Gnomad4 NFE exome AF: 0.434

Gnomad4 OTH exome AF: 0.418

GnomAD4 genome AF: 0.398 AC: 60505 AN: 152138 Hom.: 12288 Cov.: 32 AF XY: 0.399 AC XY: 29645 AN XY: 74368

Gnomad4 AFR AF: 0.346

Gnomad4 AMR AF: 0.344

Gnomad4 ASJ AF: 0.275

Gnomad4 EAS AF: 0.570

Gnomad4 SAS AF: 0.380

Gnomad4 FIN AF: 0.451

Gnomad4 NFE AF: 0.428

Gnomad4 OTH AF: 0.366

Alfa AF: 0.405 Hom.: 13226

Bravo AF: 0.387

Asia WGS AF: 0.443 AC: 1543 AN: 3478

EpiCase AF: 0.406

EpiControl AF: 0.406

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	6.6
DANN	Benign	0.74

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: rs365066; hg19: chr6-32975257;