Genetic Variant NM_002119.4:c.614-22A>G (chr6-33007237-T-C) – 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.614-22A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.418 in 1,612,856 control chromosomes in the GnomAD database, including 143,870 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. There are indicators that this mutation may affect the branch point..

Frequency

Genomes: 𝑓 0.40 ( 12293 hom., cov: 32)

Exomes 𝑓: 0.42 ( 131577 hom. )

Consequence

HLA-DOA
NM_002119.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.17

Publications

44 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

This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 0 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.92).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.554 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HLA-DOA	NM_002119.4	MANE Select	c.614-22A>G		intron	N/A	NP_002110.1	A0A1V0E3R8

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
HLA-DOA	ENST00000229829.7	TSL:6 MANE Select	c.614-22A>G	intron	N/A	ENSP00000229829.3	P06340
HLA-DOA	ENST00000892664.1		c.332-22A>G	intron	N/A	ENSP00000562723.1
HLA-DOA	ENST00000485901.1	TSL:6	n.398A>G	non_coding_transcript_exon	Exon 2 of 3

Frequencies

GnomAD3 genomes

AF:

0.398

AC:

60456

AN:

151868

Hom.:

12282

Cov.:

show subpopulations

Gnomad AFR

AF:

0.346

Gnomad AMI

AF:

0.474

Gnomad AMR

AF:

0.344

Gnomad ASJ

AF:

0.275

Gnomad EAS

AF:

0.571

Gnomad SAS

AF:

0.380

Gnomad FIN

AF:

0.452

Gnomad MID

AF:

0.326

Gnomad NFE

AF:

0.428

Gnomad OTH

AF:

0.364

GnomAD2 exomes

AF:

0.397

AC:

99000

AN:

249256

AF XY:

0.402

show subpopulations

Gnomad AFR exome

AF:

0.340

Gnomad AMR exome

AF:

0.255

Gnomad ASJ exome

AF:

0.275

Gnomad EAS exome

AF:

0.583

Gnomad FIN exome

AF:

0.446

Gnomad NFE exome

AF:

0.429

Gnomad OTH exome

AF:

0.380

GnomAD4 exome

AF:

0.420

AC:

614265

AN:

1460870

Hom.:

131577

Cov.:

AF XY:

0.420

AC XY:

304965

AN XY:

726772

show subpopulations

African (AFR)

AF:

0.337

AC:

11298

AN:

33476

American (AMR)

AF:

0.268

AC:

12004

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.280

AC:

7306

AN:

26132

East Asian (EAS)

AF:

0.469

AC:

18609

AN:

39698

South Asian (SAS)

AF:

0.369

AC:

31827

AN:

86254

European-Finnish (FIN)

AF:

0.448

AC:

23622

AN:

52780

Middle Eastern (MID)

AF:

0.338

AC:

1951

AN:

5768

European-Non Finnish (NFE)

AF:

0.434

AC:

482394

AN:

1111658

Other (OTH)

AF:

0.418

AC:

25254

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

21143

42285

63428

84570

105713

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

14624

29248

43872

58496

73120

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.398

AC:

60509

AN:

151986

Hom.:

12293

Cov.:

AF XY:

0.399

AC XY:

29651

AN XY:

74288

show subpopulations

African (AFR)

AF:

0.347

AC:

14366

AN:

41442

American (AMR)

AF:

0.344

AC:

5261

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.275

AC:

954

AN:

3470

East Asian (EAS)

AF:

0.571

AC:

2948

AN:

5164

South Asian (SAS)

AF:

0.380

AC:

1831

AN:

4818

European-Finnish (FIN)

AF:

0.452

AC:

4776

AN:

10562

Middle Eastern (MID)

AF:

0.313

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.428

AC:

29077

AN:

67922

Other (OTH)

AF:

0.367

AC:

774

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1874

3747

5621

7494

9368

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

576

1152

1728

2304

2880

<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:

0.414

Hom.:

46537

Bravo

AF:

0.387

Asia WGS

AF:

0.445

AC:

1550

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.92

CADD

Benign

0.24

(source)

DANN

Benign

0.40

PhyloP100

-2.2

BranchPoint Hunter

0.0

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over