6-33007237-T-C

Variant names:

• chr6-33007237-T-C
• rs399604
• NM_002119.4:c.614-22A>G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002119.4(HLA-DOA):​c.614-22A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.418 in 1,612,856 control chromosomes in the GnomAD database, including 143,870 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. There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.40 (12293 hom., cov: 32)
  • Exomes 𝑓: 0.42 (131577 hom.)
• Consequence: HLA-DOA NM_002119.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.17

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 -12 ACMG points.

• BP4: This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 0 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.554 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HLA-DOA	NM_002119.4	c.614-22A>G		intron_variant	Intron 3 of 4	ENST00000229829.7	NP_002110.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HLA-DOA	ENST00000229829.7	c.614-22A>G		intron_variant	Intron 3 of 4	6	NM_002119.4	ENSP00000229829.3
HLA-DOA	ENST00000485901.1	n.398A>G		non_coding_transcript_exon_variant	Exon 2 of 3	6
HLA-DOA	ENST00000490305.5	n.32-22A>G		intron_variant	Intron 1 of 2	6
HLA-DOA	ENST00000495532.1	n.*208A>G		downstream_gene_variant		6

Frequencies

GnomAD3 genomes AF: 0.398 AC: 60456 AN: 151868 Hom.: 12282 Cov.: 32

Gnomad AFR AF: 0.346

Gnomad AMI AF: 0.474

Gnomad AMR AF: 0.344

Gnomad ASJ AF: 0.275

Gnomad EAS AF: 0.571

Gnomad SAS AF: 0.380

Gnomad FIN AF: 0.452

Gnomad MID AF: 0.326

Gnomad NFE AF: 0.428

Gnomad OTH AF: 0.364

GnomAD3 exomes AF: 0.397 AC: 99000 AN: 249256 Hom.: 21085 AF XY: 0.402 AC XY: 54462 AN XY: 135346

Gnomad AFR exome AF: 0.340

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: 0.446

Gnomad NFE exome AF: 0.429

Gnomad OTH exome AF: 0.380

GnomAD4 exome AF: 0.420 AC: 614265 AN: 1460870 Hom.: 131577 Cov.: 47 AF XY: 0.420 AC XY: 304965 AN XY: 726772

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: 0.448

Gnomad4 NFE exome AF: 0.434

Gnomad4 OTH exome AF: 0.418

GnomAD4 genome AF: 0.398 AC: 60509 AN: 151986 Hom.: 12293 Cov.: 32 AF XY: 0.399 AC XY: 29651 AN XY: 74288

Gnomad4 AFR AF: 0.347

Gnomad4 AMR AF: 0.344

Gnomad4 ASJ AF: 0.275

Gnomad4 EAS AF: 0.571

Gnomad4 SAS AF: 0.380

Gnomad4 FIN AF: 0.452

Gnomad4 NFE AF: 0.428

Gnomad4 OTH AF: 0.367

Alfa AF: 0.415 Hom.: 19223

Bravo AF: 0.387

Asia WGS AF: 0.445 AC: 1550 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.24
DANN	Benign	0.40
BranchPoint Hunter		0.0

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: rs399604; hg19: chr6-32975014; COSMIC: COSV57716017; COSMIC: COSV57716017;