chr6-33008092-G-C

Variant names:

• chr6-33008092-G-C
• rs375256
• NM_002119.4:c.252C>G

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_002119.4(HLA-DOA):​c.252C>G​(p.Gly84Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. G84G) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: HLA-DOA NM_002119.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.92
• Publications: 22 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]

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.043552667).
• BP7: Synonymous conserved (PhyloP=-3.92 with no splicing effect.

Variant Effect in Transcripts

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

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HLA-DOA	NM_002119.4	MANE Select	c.252C>G	p.Gly84Gly	synonymous	Exon 2 of 5	NP_002110.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HLA-DOA	ENST00000229829.7	TSL:6 MANE Select	c.252C>G	p.Gly84Gly	synonymous	Exon 2 of 5	ENSP00000229829.3
	HLA-DOA	ENST00000374813.1	TSL:6	c.85C>G	p.Arg29Gly	missense splice_region	Exon 2 of 3	ENSP00000363946.1
	HLA-DOA	ENST00000892664.1		c.252C>G	p.Gly84Gly	synonymous	Exon 2 of 4	ENSP00000562723.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 2993

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.13
DANN	Benign	0.46
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.023	N
MetaRNN	Benign	0.044	T
MetaSVM	Benign	-1.1	T
PhyloP100		-3.9
PROVEAN	Benign	-0.14	N
REVEL	Benign	0.0030
Sift	Benign	0.20	T
MutPred		0.18		Loss of MoRF binding (P = 0.0162)
MVP		0.081
ClinPred		0.060	T
GERP RS		-9.0
Mutation Taster		=92/8	polymorphism

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

Other links and lift over

dbSNP: rs375256; hg19: chr6-32975869;