chr6-33008982-G-T

Variant names:

• chr6-33008982-G-T
• rs86567
• NM_002119.4:c.82+473C>A

GermlineCancer (beta)

Variant summary

Our verdict is Benign.

<-10 Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -12 classification points (ACMG Germline Pathogenicity v2019). BA1BP4_Strong

The NM_002119.4(HLA-DOA):c.82+473C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.619 (AC=94,082) in the gnomAD database across 151,942 control chromosomes, including 29,621 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.746. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.62 (29621 hom., cov: 31)
• Consequence: HLA-DOA NM_002119.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.194
• Publications: 36 publications found

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]

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Benign. The variant received -12 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Strong).
	BA1Stand-alone benign allele frequency (>5%)		GnomAD effective popmax AF >5% — BA1 stand-alone benign; GnomAD reliable popmax AF = 0.7456 — exceeds 5%% threshold (BA1 applied)

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_002119.4. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	HLA-DOA NM_002119.4	MANE Select	c.82+473C>A	intron	Intron 1 of 4	Prot: NP_002110.1 UniProt:

HLA-DOA NM_002119.4

MANE Select

HGVSc / HGVSpc.82+473C>A

Exon rankIntron 1 of 4

intron

Prot: NP_002110.1UniProt: P06340

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	HLA-DOA ENST00000229829.7	TSL:6MANE Select	c.82+473C>A	intron	Intron 1 of 4	Prot: ENSP00000229829.3 UniProt:
	HLA-DOA ENST00000892664.1		c.82+473C>A	intron	Intron 1 of 3	Prot: ENSP00000562723.1 UniProt:
	HLA-DOA ENST00000374813.1	TSL:6	c.82+473C>A	intron	Intron 1 of 2	Prot: ENSP00000363946.1 UniProt:

HLA-DOA ENST00000229829.7

TSL:6MANE Select

HGVSc / HGVSpc.82+473C>A

Exon rankIntron 1 of 4

intron

Prot: ENSP00000229829.3UniProt: P06340

HLA-DOA ENST00000892664.1

HGVSc / HGVSpc.82+473C>A

Exon rankIntron 1 of 3

intron

Prot: ENSP00000562723.1UniProt: A0ACI8QSL6

HLA-DOA ENST00000374813.1

TSL:6

HGVSc / HGVSpc.82+473C>A

Exon rankIntron 1 of 2

intron

Prot: ENSP00000363946.1UniProt: F6WU08

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 4 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.619	AC:94008	Hom:29592	AN:151824	Cov:31
GnomAD4 genome	AF: 0.619	AC:94082	Hom:29621	AN:151942	Cov:31
TOPMed (Bravo)	AF: 0.613	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.587	AC:370614	Hom:110741	AN:631630	Cov:
Local & regional cohorts 8 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	AF: 0.629	AC:1473	Hom:466	AN:2342	Cov:
GenomeAsia100K	AF: 0.710	AC:2468	Hom:	AN:3478	Cov:
Korea4K (4,157 Koreans)	AF: 0.638	AC:4614	Hom:	AN:7234	Cov:
Qatari Genome	AF: 0.756	AC:133	Hom:	AN:176	Cov:
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.693	AC:85011	Hom:29488	AN:122734	Cov:
Turkish Variome	AF: 0.654	AC:1010	Hom:336	AN:1544	Cov:
UK10K	AF: 0.569	AC:4305	Hom:	AN:7562	Cov:
WBBC (Westlake BioBank for Chinese) pilot	AF: 0.497	AC:4452	Hom:1099	AN:8960	Cov:

Showing 12 sources

Tested, but no data found:GnomAD4 exomeIf GnomAD4 is missing, the position is probably not covered by the project.

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Benign	2.3
BayesDel_noAF	Benign	-0.84
CADD	Benign	1.8
DANN	Benign	0.49
GPN-Star LLR	N/A	3.0
GPN-Star score	N/A	-0.74
Mutation Taster	N/A	100/0	polymorphism (auto)
PhyloP100	Benign	-0.19

Showing 8 of 8 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs86567;

hg19: chr6-32976759;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar