Genetic Variant HLA-DOA:c.*1973G>A (chr6-33004865-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_002119.4(HLA-DOA):c.*1973G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.125 in 152,274 control chromosomes in the GnomAD database, including 1,439 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.12 ( 1438 hom., cov: 32)

Exomes 𝑓: 0.089 ( 1 hom. )

Consequence

HLA-DOA
NM_002119.4 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0850

Publications

33 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.83).

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.255 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HLA-DOA	NM_002119.4 link	c.*1973G>A		3_prime_UTR_variant	Exon 5 of 5	ENST00000229829.7	NP_002110.1	P06340X5CF87A0A1V0E3Q8A0A1V0E3Q5A0A1V0E3N1A0A1V0E3M7A0A1V0E3R3A0A1V0E3S6A0A1V0E3T1A0A1V0E3P8A0A1V0E3Q2A0A1V0E3P6A0A1V0E3S7A0A1V0E3P1A0A1V0E3Q6A0A1V0E3P3A0A1V0E3R6A0A1V0E3P9A0A1V0E3N7A0A1V0E3S0A0A1V0E3Q1A0A1V0E3N3A0A1V0E3Q4A0A1V0E3R4A0A1V0E3P0A0A1V0E3R0A0A1V0E3N6A0A1V0E3R8A0A1V0E3S4A0A1V0E3Q7A0A1V0E3Q3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HLA-DOA	ENST00000229829.7 link	c.*1973G>A		3_prime_UTR_variant	Exon 5 of 5	6	NM_002119.4	ENSP00000229829.3		P06340

Frequencies

GnomAD3 genomes

AF:

0.125

AC:

19008

AN:

152100

Hom.:

1439

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0569

Gnomad AMI

AF:

0.152

Gnomad AMR

AF:

0.126

Gnomad ASJ

AF:

0.288

Gnomad EAS

AF:

0.243

Gnomad SAS

AF:

0.268

Gnomad FIN

AF:

0.117

Gnomad MID

AF:

0.203

Gnomad NFE

AF:

0.138

Gnomad OTH

AF:

0.149

GnomAD4 exome

AF:

0.0893

AC:

AN:

Hom.:

Cov.:

AF XY:

0.0435

AC XY:

AN XY:

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AF:

0.00

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AF:

0.500

AC:

AN:

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.0833

AC:

AN:

Other (OTH)

AC:

AN:

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0628932), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.125

AC:

19022

AN:

152218

Hom.:

1438

Cov.:

AF XY:

0.130

AC XY:

9651

AN XY:

74414

show subpopulations

African (AFR)

AF:

0.0571

AC:

2371

AN:

41546

American (AMR)

AF:

0.127

AC:

1939

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.288

AC:

998

AN:

3470

East Asian (EAS)

AF:

0.242

AC:

1255

AN:

5176

South Asian (SAS)

AF:

0.268

AC:

1290

AN:

4820

European-Finnish (FIN)

AF:

0.117

AC:

1244

AN:

10590

Middle Eastern (MID)

AF:

0.204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.138

AC:

9407

AN:

67994

Other (OTH)

AF:

0.151

AC:

319

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

864

1728

2593

3457

4321

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

240

480

720

960

1200

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.144

Hom.:

7461

Bravo

AF:

0.122

Asia WGS

AF:

0.267

AC:

929

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

1.9

(source)

DANN

Benign

0.47

PhyloP100

-0.085

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over