1-1512287-A-G

Position:

chr1-1512287-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001170535.3(ATAD3A):c.19A>G(p.Ile7Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0102 in 151,686 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.010 ( 13 hom., cov: 32)

Exomes 𝑓: 0.0042 ( 140 hom. )

Failed GnomAD Quality Control

Consequence

ATAD3A
NM_001170535.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.859

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 Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0049882233).

BP6

Variant 1-1512287-A-G is Benign according to our data. Variant chr1-1512287-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 1675332.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0102 (1552/151686) while in subpopulation AMR AF= 0.0132 (201/15258). AF 95% confidence interval is 0.0123. There are 13 homozygotes in gnomad4. There are 730 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 13 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATAD3A	NM_001170535.3 linkuse as main transcript	c.19A>G	p.Ile7Val	missense_variant	1/16	ENST00000378756.8	NP_001164006.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATAD3A	ENST00000378756.8 linkuse as main transcript	c.19A>G	p.Ile7Val	missense_variant	1/16	1	NM_001170535.3	ENSP00000368031	P1	Q9NVI7-2
ATAD3A	ENST00000378755.9 linkuse as main transcript	c.19A>G	p.Ile7Val	missense_variant	1/16	2		ENSP00000368030		Q9NVI7-1
ATAD3A	ENST00000672388.1 linkuse as main transcript	n.123A>G		non_coding_transcript_exon_variant	1/14

Frequencies

GnomAD3 genomes

AF:

0.0102

AC:

1551

AN:

151586

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00751

Gnomad AMI

AF:

0.00329

Gnomad AMR

AF:

0.0133

Gnomad ASJ

AF:

0.00375

Gnomad EAS

AF:

0.000981

Gnomad SAS

AF:

0.0123

Gnomad FIN

AF:

0.00521

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0130

Gnomad OTH

AF:

0.00961

GnomAD3 exomes

AF:

0.00329

AC:

184

AN:

55982

Hom.:

AF XY:

0.00299

AC XY:

AN XY:

31408

show subpopulations

Gnomad AFR exome

AF:

0.00418

Gnomad AMR exome

AF:

0.00210

Gnomad ASJ exome

AF:

0.00135

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00536

Gnomad FIN exome

AF:

0.00289

Gnomad NFE exome

AF:

0.00371

Gnomad OTH exome

AF:

0.00243

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00418

AC:

4596

AN:

1100304

Hom.:

140

Cov.:

AF XY:

0.00422

AC XY:

2213

AN XY:

524940

show subpopulations

Gnomad4 AFR exome

AF:

0.00302

Gnomad4 AMR exome

AF:

0.00483

Gnomad4 ASJ exome

AF:

0.00419

Gnomad4 EAS exome

AF:

0.0000715

Gnomad4 SAS exome

AF:

0.00415

Gnomad4 FIN exome

AF:

0.00615

Gnomad4 NFE exome

AF:

0.00420

Gnomad4 OTH exome

AF:

0.00533

GnomAD4 genome

AF:

0.0102

AC:

1552

AN:

151686

Hom.:

Cov.:

AF XY:

0.00985

AC XY:

730

AN XY:

74140

show subpopulations

Gnomad4 AFR

AF:

0.00749

Gnomad4 AMR

AF:

0.0132

Gnomad4 ASJ

AF:

0.00375

Gnomad4 EAS

AF:

0.000984

Gnomad4 SAS

AF:

0.0127

Gnomad4 FIN

AF:

0.00521

Gnomad4 NFE

AF:

0.0130

Gnomad4 OTH

AF:

0.00951

Alfa

AF:

0.00434

Hom.:

Bravo

AF:

0.0104

ExAC

AF:

0.00242

AC:

247

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	ATAD3A: BS1, BS2 -

Harel-Yoon syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Molecular Genetics, Royal Melbourne Hospital

May 04, 2023

African/African American population allele frequency is 1.231% (rs201315462, 884/67870 alleles, 8 homozygotes in gnomAD v3.1). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.5.1, this variant is classified as BENIGN. Following criteria are met: BA1 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.097

BayesDel_addAF

Benign

-0.10

BayesDel_noAF

Benign

-0.39

CADD

Benign

DANN

Benign

0.51

DEOGEN2

Benign

0.0059

.;T

Eigen

Benign

-1.1

Eigen_PC

Benign

-0.98

FATHMM_MKL

Benign

0.65

LIST_S2

Benign

0.65

T;T

MetaRNN

Benign

0.0050

T;T

MetaSVM

Benign

-0.81

MutationAssessor

Benign

0.34

N;N

MutationTaster

Benign

0.74

N;N

PrimateAI

Pathogenic

0.82

PROVEAN

Benign

-0.20

N;N

REVEL

Benign

0.28

Sift

Benign

0.55

T;T

Sift4G

Benign

0.55

T;T

Polyphen

0.0

.;B

Vest4

0.11

MVP

0.44

MPC

0.28

ClinPred

0.00089

GERP RS

-2.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.040

gMVP

0.19

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