Genetic Variant HLA-DOA:c.82+473C>G (chr6-33008982-G-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is The variant received -2 classification points (ACMG Germline Pathogenicity v2019). PM2BP4_Strong

The NM_002119.4(HLA-DOA):c.82+473C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.0000263 (AC=4) in the gnomAD database across 151,880 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.0000326. 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 0.000026 ( 0 hom., cov: 31)

Consequence

HLA-DOA
NM_002119.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.194

Publications

36 publications found

Variant links:

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]

HLA-DOA links:

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new If you want to explore the variant's impact on the transcript NM_002119.4, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Likely_benign. The variant received -2 points.

Show applied only (2)

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		Very rare in gnomAD for AR/unknown gene (popmax AF < threshold/10) — PM2; GnomAD popmax AF = 0.0000326 — very rare for unknown gene (threshold 0.001) — PM2 moderate.
	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).

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>G	intron	Intron 1 of 4	Prot: NP_002110.1 UniProt: P06340

HLA-DOA NM_002119.4

MANE Select

HGVSc / HGVSpc.82+473C>G

Exon rankIntron 1 of 4

intron

Prot: NP_002110.1UniProt: P06340

Ensembl Transcripts

Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
HLA-DOA ENST00000229829.7	TSL:6MANE Select	c.82+473C>G	intron	Intron 1 of 4	Prot: ENSP00000229829.3 UniProt: P06340
HLA-DOA ENST00000892664.1		c.82+473C>G	intron	Intron 1 of 3	Prot: ENSP00000562723.1 UniProt: A0ACI8QSL6
HLA-DOA ENST00000374813.1	TSL:6	c.82+473C>G	intron	Intron 1 of 2	Prot: ENSP00000363946.1 UniProt: F6WU08

HLA-DOA ENST00000229829.7

TSL:6MANE Select

HGVSc / HGVSpc.82+473C>G

Exon rankIntron 1 of 4

intron

Prot: ENSP00000229829.3UniProt: P06340

HLA-DOA ENST00000892664.1

HGVSc / HGVSpc.82+473C>G

Exon rankIntron 1 of 3

intron

Prot: ENSP00000562723.1UniProt: A0ACI8QSL6

HLA-DOA ENST00000374813.1

TSL:6

HGVSc / HGVSpc.82+473C>G

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: 0.0000263	AC:4	Hom:0	AN:151880	Cov:31
GnomAD4 genome	AF: 0.0000263	AC:4	Hom:0	AN:151880	Cov:31
TOPMed (Bravo)	AF: 0.0000491	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.00	AC:0	Hom:110741	AN:631630	Cov:

Showing 4 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
AlphaGenome AVI	Benign	3.3
BayesDel_noAF	Benign	-0.89
CADD	Benign	2.0
DANN	Benign	0.22
GPN-Star LLR	N/A	3.2
GPN-Star score	N/A	-0.63
PhyloP100	Benign	-0.19

Showing 7 of 7 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.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

Classification according to ACMG Germline Pathogenicity v2019

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational Scores

Splicing Scores

MaveDB functional evidence ?

Publications

Other links and lift over

MaveDB functional evidence