rs375256

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr6-33008092-G-A
• chr6-33008092-G-C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The ENST00000229829.7(HLA-DOA):​c.252C>T​(p.Gly84Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.236 in 1,612,792 control chromosomes in the GnomAD database, including 47,458 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as (no stars).

• Frequency:
  • Genomes: 𝑓 0.20 (3711 hom., cov: 33)
  • Exomes 𝑓: 0.24 (43747 hom.)
• Consequence: HLA-DOA ENST00000229829.7 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0011001527).
• BP7: Synonymous conserved (PhyloP=-3.92 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.373 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000229829.7. 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>T	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>T	p.Gly84Gly	synonymous	Exon 2 of 5	ENSP00000229829.3
	HLA-DOA	ENST00000374813.1	TSL:6	c.85C>T	p.Arg29Trp	missense splice_region	Exon 2 of 3	ENSP00000363946.1
	HLA-DOA	ENST00000467465.1	TSL:6	n.441C>T		non_coding_transcript_exon	Exon 2 of 2

Frequencies

GnomAD3 genomes AF: 0.204 AC: 31031 AN: 152052 Hom.: 3704 Cov.: 33

Gnomad AFR AF: 0.0997

Gnomad AMI AF: 0.259

Gnomad AMR AF: 0.170

Gnomad ASJ AF: 0.106

Gnomad EAS AF: 0.386

Gnomad SAS AF: 0.188

Gnomad FIN AF: 0.280

Gnomad MID AF: 0.123

Gnomad NFE AF: 0.256

Gnomad OTH AF: 0.171

GnomAD2 exomes AF: 0.229 AC: 56426 AN: 246120 AF XY: 0.233

Gnomad AFR exome AF: 0.0950

Gnomad AMR exome AF: 0.136

Gnomad ASJ exome AF: 0.0995

Gnomad EAS exome AF: 0.417

Gnomad FIN exome AF: 0.279

Gnomad NFE exome AF: 0.261

Gnomad OTH exome AF: 0.214

GnomAD4 exome AF: 0.240 AC: 350241 AN: 1460622 Hom.: 43747 Cov.: 36 AF XY: 0.239 AC XY: 173799 AN XY: 726624

African (AFR) AF: 0.0973 AC: 3256 AN: 33480

American (AMR) AF: 0.139 AC: 6223 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.103 AC: 2701 AN: 26134

East Asian (EAS) AF: 0.325 AC: 12910 AN: 39696

South Asian (SAS) AF: 0.183 AC: 15799 AN: 86256

European-Finnish (FIN) AF: 0.280 AC: 14636 AN: 52240

Middle Eastern (MID) AF: 0.149 AC: 859 AN: 5768

European-Non Finnish (NFE) AF: 0.252 AC: 280323 AN: 1111950

Other (OTH) AF: 0.224 AC: 13534 AN: 60386

GnomAD4 genome AF: 0.204 AC: 31063 AN: 152170 Hom.: 3711 Cov.: 33 AF XY: 0.206 AC XY: 15311 AN XY: 74396

African (AFR) AF: 0.100 AC: 4156 AN: 41536

American (AMR) AF: 0.170 AC: 2607 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.106 AC: 368 AN: 3472

East Asian (EAS) AF: 0.387 AC: 1997 AN: 5154

South Asian (SAS) AF: 0.187 AC: 902 AN: 4826

European-Finnish (FIN) AF: 0.280 AC: 2971 AN: 10610

Middle Eastern (MID) AF: 0.122 AC: 36 AN: 294

European-Non Finnish (NFE) AF: 0.256 AC: 17422 AN: 67956

Other (OTH) AF: 0.175 AC: 369 AN: 2114

Alfa AF: 0.212 Hom.: 2993

Bravo AF: 0.192

TwinsUK AF: 0.252 AC: 934

ALSPAC AF: 0.245 AC: 943

ESP6500AA AF: 0.101 AC: 306

ESP6500EA AF: 0.255 AC: 1384

ExAC AF: 0.234 AC: 27538

Asia WGS AF: 0.229 AC: 797 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Benign	-0.87	T
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.20
DANN	Benign	0.62
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.0082	N
MetaRNN	Benign	0.0011	T
MetaSVM	Benign	-1.0	T
PhyloP100		-3.9
PROVEAN	Benign	0.17	N
REVEL	Benign	0.013
Sift	Benign	0.047	D
ClinPred		0.020	T
GERP RS		-9.0
Mutation Taster		=97/3	polymorphism (auto)

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; COSMIC: COSV57714277; COSMIC: COSV57714277;