1-1534004-C-T

Position:

chr1-1534004-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2BP4BP6BS1

The NM_001170535.3(ATAD3A):c.1693C>T(p.His565Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.000492 in 1,613,606 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00030 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00051 ( 1 hom. )

Consequence

ATAD3A
NM_001170535.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 5.66

Variant links:

Genes affected

ATAD3A (HGNC:25567): (ATPase family AAA domain containing 3A) This gene encodes a ubiquitously expressed mitochondrial membrane protein that contributes to mitochondrial dynamics, nucleoid organization, protein translation, cell growth, and cholesterol metabolism. This gene is a member of the ATPase family AAA-domain containing 3 gene family which, in humans, includes two other paralogs. Naturally occurring mutations in this gene are associated with distinct neurological syndromes including Harel-Yoon syndrome. High-level expression of this gene is associated with poor survival in breast cancer patients. A homozygous knockout of the orthologous gene in mice results in embryonic lethality at day 7.5 due to growth retardation and defective development of the trophoblast lineage. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2017]

ATAD3A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.28841603).

BP6

Variant 1-1534004-C-T is Benign according to our data. Variant chr1-1534004-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 522903.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=1}.

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000295 (45/152298) while in subpopulation SAS AF= 0.000621 (3/4830). AF 95% confidence interval is 0.000368. There are 0 homozygotes in gnomad4. There are 22 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
ATAD3A	NM_001170535.3 link	c.1693C>T	p.His565Tyr	missense_variant	16/16	ENST00000378756.8	NP_001164006.1
ATAD3A	NM_018188.5 link	c.1837C>T	p.His613Tyr	missense_variant	16/16		NP_060658.3
ATAD3A	NM_001170536.3 link	c.1456C>T	p.His486Tyr	missense_variant	16/16		NP_001164007.1
ATAD3A	XM_047424288.1 link	c.1531C>T	p.His511Tyr	missense_variant	17/17		XP_047280244.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATAD3A	ENST00000378756.8 link	c.1693C>T	p.His565Tyr	missense_variant	16/16	1	NM_001170535.3	ENSP00000368031.3		Q9NVI7-2

Frequencies

GnomAD3 genomes

AF:

0.000296

AC:

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000500

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000283

AC:

AN:

250764

Hom.:

AF XY:

0.000273

AC XY:

AN XY:

135778

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.000174

Gnomad ASJ exome

AF:

0.000199

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.000555

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000362

Gnomad OTH exome

AF:

0.000327

GnomAD4 exome

AF:

0.000513

AC:

749

AN:

1461308

Hom.:

Cov.:

AF XY:

0.000499

AC XY:

363

AN XY:

727004

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.000201

Gnomad4 ASJ exome

AF:

0.000191

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000348

Gnomad4 FIN exome

AF:

0.0000189

Gnomad4 NFE exome

AF:

0.000595

Gnomad4 OTH exome

AF:

0.000530

GnomAD4 genome

AF:

0.000295

AC:

AN:

152298

Hom.:

Cov.:

AF XY:

0.000295

AC XY:

AN XY:

74480

show subpopulations

Gnomad4 AFR

AF:

0.0000722

Gnomad4 AMR

AF:

0.000261

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000621

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000500

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000126

Hom.:

Bravo

AF:

0.000276

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000272

AC:

EpiCase

AF:

0.000327

EpiControl

AF:

0.000474

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Harel-Yoon syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genomic Research Center, Shahid Beheshti University of Medical Sciences

May 03, 2020

- -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 16, 2022

Unlikely to be causative of AD ATAD3A-related mitochondrial disorder. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jan 01, 2023

ATAD3A: BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

BayesDel_addAF

Uncertain

0.023

BayesDel_noAF

Pathogenic

0.14

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.12

.;T;.

Eigen

Benign

-0.042

Eigen_PC

Benign

0.019

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.81

T;T;T

M_CAP

Pathogenic

0.40

MetaRNN

Benign

0.29

T;T;T

MetaSVM

Uncertain

0.63

MutationAssessor

Uncertain

2.2

.;M;.

PrimateAI

Uncertain

0.67

PROVEAN

Pathogenic

-4.6

D;D;D

REVEL

Uncertain

0.54

Sift

Benign

0.055

T;T;D

Sift4G

Uncertain

0.027

D;D;D

Polyphen

0.0020

.;B;.

Vest4

0.53

MVP

0.91

MPC

0.55

ClinPred

0.56

GERP RS

3.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.9

Varity_R

0.59

gMVP

0.86

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