Genetic Variant ATAD3B:p.Gly28Arg (chr1-1471966-G-A) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_031921.6(ATAD3B):c.82G>A(p.Gly28Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000407 in 1,241,768 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00051 ( 2 hom., cov: 30)

Exomes 𝑓: 0.00039 ( 1 hom. )

Consequence

ATAD3B
NM_031921.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.36

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 made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.19638473).

BS2

High Homozygotes in GnomAd4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATAD3B	NM_031921.6 link	c.82G>A	p.Gly28Arg	missense_variant	Exon 1 of 16	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.82G>A	p.Gly28Arg	missense_variant	Exon 1 of 16		NM_031921.6	ENSP00000500094.1		Q5T9A4-1
ATAD3B	ENST00000308647.8 link	c.82G>A	p.Gly28Arg	missense_variant	Exon 1 of 14	1		ENSP00000311766.8		A0A5K1VW56

Frequencies

GnomAD3 genomes

AF:

0.000510

AC:

AN:

150988

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000390

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000660

Gnomad ASJ

AF:

0.00779

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00356

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000192

Gnomad OTH

AF:

0.00144

GnomAD4 exome

AF:

0.000392

AC:

428

AN:

1090676

Hom.:

Cov.:

AF XY:

0.000408

AC XY:

211

AN XY:

517064

show subpopulations

Gnomad4 AFR exome

AF:

0.000492

Gnomad4 AMR exome

AF:

0.000124

Gnomad4 ASJ exome

AF:

0.00919

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00361

Gnomad4 FIN exome

AF:

0.0000298

Gnomad4 NFE exome

AF:

0.000171

Gnomad4 OTH exome

AF:

0.00111

GnomAD4 genome

AF:

0.000510

AC:

AN:

151092

Hom.:

Cov.:

AF XY:

0.000528

AC XY:

AN XY:

73850

show subpopulations

Gnomad4 AFR

AF:

0.000413

Gnomad4 AMR

AF:

0.0000659

Gnomad4 ASJ

AF:

0.00779

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00335

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000192

Gnomad4 OTH

AF:

0.00143

Alfa

AF:

0.000641

Hom.:

Bravo

AF:

0.000423

ExAC

AF:

0.000299

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 02, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.82G>A (p.G28R) alteration is located in exon 1 (coding exon 1) of the ATAD3B gene. This alteration results from a G to A substitution at nucleotide position 82, causing the glycine (G) at amino acid position 28 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Uncertain

0.0

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.046

Eigen

Uncertain

0.35

Eigen_PC

Uncertain

0.24

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.83

M_CAP

Pathogenic

0.96

MetaRNN

Benign

0.20

MetaSVM

Uncertain

0.75

MutationAssessor

Benign

1.8

PrimateAI

Pathogenic

0.90

PROVEAN

Benign

-2.0

REVEL

Uncertain

0.53

Sift

Benign

0.068

Sift4G

Uncertain

0.013

Polyphen

0.99

Vest4

0.38

MutPred

0.24

Gain of solvent accessibility (P = 0.0171);

MVP

0.80

MPC

2.1

ClinPred

0.89

GERP RS

2.6

Varity_R

0.11

gMVP

0.056

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over