Genetic Variant ATAD3B:p.Glu88Lys (chr1-1477330-G-A) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_031921.6(ATAD3B):c.262G>A(p.Glu88Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,459,994 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

ATAD3B
NM_031921.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.98

Publications

1 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: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.773

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_031921.6. 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
	ATAD3B	NM_031921.6	MANE Select	c.262G>A	p.Glu88Lys	missense	Exon 2 of 16	NP_114127.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ATAD3B	ENST00000673477.1	MANE Select	c.262G>A	p.Glu88Lys	missense	Exon 2 of 16	ENSP00000500094.1	Q5T9A4-1
ATAD3B	ENST00000308647.8	TSL:1	c.262G>A	p.Glu88Lys	missense	Exon 2 of 14	ENSP00000311766.8	A0A5K1VW56
ATAD3B	ENST00000940534.1		c.262G>A	p.Glu88Lys	missense	Exon 2 of 17	ENSP00000610593.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000120

AC:

AN:

250960

AF XY:

0.0000147

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000265

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1459994

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726308

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:

33430

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86130

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53402

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4512

European-Non Finnish (NFE)

AF:

0.00000270

AC:

AN:

1111716

Other (OTH)

AF:

0.00

AC:

AN:

60250

⚠️ 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: 0.342

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.45

BayesDel_addAF

Benign

-0.096

BayesDel_noAF

Benign

-0.31

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.14

Eigen

Uncertain

0.48

Eigen_PC

Uncertain

0.31

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.97

M_CAP

Benign

0.029

MetaRNN

Pathogenic

0.77

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.7

PhyloP100

8.0

PrimateAI

Pathogenic

0.86

PROVEAN

Uncertain

-3.5

REVEL

Benign

0.25

Sift

Uncertain

0.0030

Sift4G

Uncertain

0.037

Polyphen

1.0

Vest4

0.80

MutPred

0.25

Gain of ubiquitination at E88 (P = 0.0037)

MVP

0.69

MPC

2.1

ClinPred

0.92

GERP RS

2.9

Varity_R

0.63

gMVP

0.24

Mutation Taster

=235/65

polymorphism

(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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over