dbSNP rs1622213: ATAD3B:c.907-5G>A (chr1-1485777-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_031921.6(ATAD3B):c.907-5G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00835 in 1,610,472 control chromosomes in the GnomAD database, including 308 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.016 ( 72 hom., cov: 32)

Exomes 𝑓: 0.0075 ( 236 hom. )

Consequence

ATAD3B
NM_031921.6 splice_region, intron

Scores

Splicing: ADA: 0.3048

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.28

Publications

7 publications found

Variant links:

Genes affected

ATAD3B (HGNC:24007): (ATPase family AAA domain containing 3B) The protein encoded by this gene is localized to the mitochondrial inner membrane, where it can bind to a highly-related protein, ATAD3A. ATAD3A appears to interact with matrix nucleoid complexes, and the encoded protein negatively regulates that interaction. This gene is expressed almost exclusively in pluripotent embryonic stem cells and some cancer cells. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Nov 2015]

ATAD3B links:

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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=-0.86).

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0164 (2485/151910) while in subpopulation AFR AF = 0.041 (1697/41440). AF 95% confidence interval is 0.0393. There are 72 homozygotes in GnomAd4. There are 1239 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 72 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATAD3B	NM_031921.6 link	c.907-5G>A		splice_region_variant, intron_variant	Intron 8 of 15	ENST00000673477.1	NP_114127.3	Q5T9A4-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATAD3B	ENST00000673477.1 link	c.907-5G>A		splice_region_variant, intron_variant	Intron 8 of 15		NM_031921.6	ENSP00000500094.1		Q5T9A4-1

Frequencies

GnomAD3 genomes

AF:

0.0164

AC:

2482

AN:

151794

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0410

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00539

Gnomad ASJ

AF:

0.00606

Gnomad EAS

AF:

0.000387

Gnomad SAS

AF:

0.00208

Gnomad FIN

AF:

0.0144

Gnomad MID

AF:

0.00637

Gnomad NFE

AF:

0.00720

Gnomad OTH

AF:

0.0149

GnomAD2 exomes

AF:

0.00690

AC:

1711

AN:

248126

AF XY:

0.00638

show subpopulations

Gnomad AFR exome

AF:

0.0293

Gnomad AMR exome

AF:

0.00444

Gnomad ASJ exome

AF:

0.00742

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0154

Gnomad NFE exome

AF:

0.00529

Gnomad OTH exome

AF:

0.00661

GnomAD4 exome

AF:

0.00751

AC:

10958

AN:

1458562

Hom.:

236

Cov.:

AF XY:

0.00715

AC XY:

5188

AN XY:

725584

show subpopulations

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

African (AFR)

AF:

0.0359

AC:

1191

AN:

33184

American (AMR)

AF:

0.00466

AC:

208

AN:

44658

Ashkenazi Jewish (ASJ)

AF:

0.00801

AC:

209

AN:

26090

East Asian (EAS)

AF:

0.000151

AC:

AN:

39690

South Asian (SAS)

AF:

0.00215

AC:

185

AN:

86126

European-Finnish (FIN)

AF:

0.0158

AC:

840

AN:

53284

Middle Eastern (MID)

AF:

0.00142

AC:

AN:

5650

European-Non Finnish (NFE)

AF:

0.00715

AC:

7930

AN:

1109640

Other (OTH)

AF:

0.00632

AC:

381

AN:

60240

⚠️ 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: 0.348

Heterozygous variant carriers

584

1169

1753

2338

2922

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

326

652

978

1304

1630

<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:

0.0164

AC:

2485

AN:

151910

Hom.:

Cov.:

AF XY:

0.0167

AC XY:

1239

AN XY:

74238

show subpopulations

African (AFR)

AF:

0.0410

AC:

1697

AN:

41440

American (AMR)

AF:

0.00538

AC:

AN:

15234

Ashkenazi Jewish (ASJ)

AF:

0.00606

AC:

AN:

3466

East Asian (EAS)

AF:

0.000388

AC:

AN:

5152

South Asian (SAS)

AF:

0.00209

AC:

AN:

4796

European-Finnish (FIN)

AF:

0.0144

AC:

152

AN:

10590

Middle Eastern (MID)

AF:

0.00685

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00717

AC:

487

AN:

67920

Other (OTH)

AF:

0.0147

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

117

234

351

468

585

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

112

140

<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:

0.00571

Hom.:

Bravo

AF:

0.0172

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

(source)

DANN

Benign

0.63

PhyloP100

-2.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.30

dbscSNV1_RF

Benign

0.54

SpliceAI score (max)

0.99

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.99

Position offset: 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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over