6-33007564-C-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BA1

The NM_002119.4(HLA-DOA):c.360G>A(p.Lys120=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00613 in 1,612,550 control chromosomes in the GnomAD database, including 534 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.031 (242 hom., cov: 33)
  • Exomes 𝑓: 0.0035 (292 hom.)
• Consequence: HLA-DOA NM_002119.4 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.471

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 -15 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0015556812).
• BP6: Variant 6-33007564-C-T is Benign according to our data. Variant chr6-33007564-C-T is described in ClinVar as [Benign]. Clinvar id is 792038.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.471 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.102 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HLA-DOA	NM_002119.4	c.360G>A	p.Lys120=	synonymous_variant	3/5	ENST00000229829.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HLA-DOA	ENST00000229829.7	c.360G>A	p.Lys120=	synonymous_variant	3/5		NM_002119.4	P1
HLA-DOA	ENST00000374813.1	c.193G>A	p.Val65Ile	missense_variant	3/3
HLA-DOA	ENST00000485901.1	n.71G>A		non_coding_transcript_exon_variant	2/3
HLA-DOA	ENST00000495532.1	n.426G>A		non_coding_transcript_exon_variant	2/2

Frequencies

GnomAD3 genomes AF: 0.0312 AC: 4743 AN: 152156 Hom.: 241 Cov.: 33

Gnomad AFR AF: 0.105

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0192

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000309

Gnomad OTH AF: 0.0344

GnomAD3 exomes AF: 0.00798 AC: 1959 AN: 245516 Hom.: 92 AF XY: 0.00597 AC XY: 799 AN XY: 133830

Gnomad AFR exome AF: 0.112

Gnomad AMR exome AF: 0.00547

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000957

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000173

Gnomad OTH exome AF: 0.00447

GnomAD4 exome AF: 0.00351 AC: 5129 AN: 1460276 Hom.: 292 Cov.: 54 AF XY: 0.00302 AC XY: 2192 AN XY: 726418

Gnomad4 AFR exome AF: 0.124

Gnomad4 AMR exome AF: 0.00692

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000986

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000729

Gnomad4 OTH exome AF: 0.00776

GnomAD4 genome AF: 0.0312 AC: 4758 AN: 152274 Hom.: 242 Cov.: 33 AF XY: 0.0304 AC XY: 2266 AN XY: 74456

Gnomad4 AFR AF: 0.105

Gnomad4 AMR AF: 0.0192

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00103

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000309

Gnomad4 OTH AF: 0.0341

Alfa AF: 0.00860 Hom.: 61

Bravo AF: 0.0374

ESP6500AA AF: 0.116 AC: 351

ESP6500EA AF: 0.000369 AC: 2

ExAC AF: 0.00952 AC: 1124

Asia WGS AF: 0.00462 AC: 17 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jun 21, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.39
Cadd	Benign	12
Dann	Benign	0.96
Eigen	Benign	0.054
Eigen_PC	Benign	0.046
FATHMM_MKL	Benign	0.18	N
MetaRNN	Benign	0.0016	T
MetaSVM	Benign	-0.81	T
MutationTaster	Benign	4.6e-10	P;P
PROVEAN	Benign	-0.17	N
REVEL	Benign	0.063
Sift	Pathogenic	0.0	D
MVP		0.088
ClinPred		0.038	T
GERP RS		4.5

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs10947368; hg19: chr6-32975341;