dbSNP rs9276977: HLA-DOA:c.*774C>T (chr6-33006064-G-A) – 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.*774C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.224 in 152,134 control chromosomes in the GnomAD database, including 3,989 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 0.22 ( 3989 hom., cov: 32)

Exomes 𝑓: 0.038 ( 0 hom. )

Consequence

HLA-DOA
NM_002119.4 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.481

Publications

19 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=-0.85).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.265 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.*774C>T		3_prime_UTR	Exon 5 of 5	NP_002110.1	A0A1V0E3R8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HLA-DOA	ENST00000229829.7	TSL:6 MANE Select	c.*774C>T		3_prime_UTR	Exon 5 of 5	ENSP00000229829.3	P06340
	HLA-DOA	ENST00000892664.1		c.*774C>T		3_prime_UTR	Exon 4 of 4	ENSP00000562723.1

Frequencies

GnomAD3 genomes

AF:

0.224

AC:

34028

AN:

151990

Hom.:

3983

Cov.:

show subpopulations

Gnomad AFR

AF:

0.270

Gnomad AMI

AF:

0.161

Gnomad AMR

AF:

0.197

Gnomad ASJ

AF:

0.190

Gnomad EAS

AF:

0.201

Gnomad SAS

AF:

0.255

Gnomad FIN

AF:

0.183

Gnomad MID

AF:

0.237

Gnomad NFE

AF:

0.211

Gnomad OTH

AF:

0.222

GnomAD4 exome

AF:

0.0385

AC:

AN:

Hom.:

Cov.:

AF XY:

0.0714

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)

AC:

AN:

American (AMR)

AF:

0.00

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

Other (OTH)

AF:

0.500

AC:

AN:

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), 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

Age Distribution

Exome Het

Variant carriers

<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:

0.224

AC:

34055

AN:

152108

Hom.:

3989

Cov.:

AF XY:

0.222

AC XY:

16509

AN XY:

74338

show subpopulations

African (AFR)

AF:

0.270

AC:

11174

AN:

41456

American (AMR)

AF:

0.197

AC:

3013

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.190

AC:

659

AN:

3472

East Asian (EAS)

AF:

0.200

AC:

1037

AN:

5176

South Asian (SAS)

AF:

0.256

AC:

1235

AN:

4820

European-Finnish (FIN)

AF:

0.183

AC:

1929

AN:

10568

Middle Eastern (MID)

AF:

0.224

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.211

AC:

14329

AN:

68002

Other (OTH)

AF:

0.220

AC:

466

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1323

2647

3970

5294

6617

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

356

712

1068

1424

1780

<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:

0.209

Hom.:

8103

Bravo

AF:

0.225

Asia WGS

AF:

0.254

AC:

885

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

4.5

(source)

DANN

Benign

0.79

PhyloP100

0.48

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over