rs1057517686

Positions:

• chr1-1529299-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_001170535.3(ATAD3A):​c.1582C>T​(p.Arg528Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R528Q) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ATAD3A NM_001170535.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 1.36

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]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-1529300-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1679823.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.942
• PP5: Variant 1-1529299-C-T is Pathogenic according to our data. Variant chr1-1529299-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 225696.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-1529299-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATAD3A	NM_001170535.3	c.1582C>T	p.Arg528Trp	missense_variant	15/16	ENST00000378756.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATAD3A	ENST00000378756.8	c.1582C>T	p.Arg528Trp	missense_variant	15/16	1	NM_001170535.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Harel-Yoon syndrome Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	Provincial Medical Genetics Program of British Columbia, University of British Columbia	Jan 01, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	Feb 08, 2018	This variant has been previously reported as a de novo change in multiple unrelated individuals with developmental delay and additional features (PMID: 27640307). An analysis of fibroblasts derived from an affected individual with this variant and the features of Harel-Yoon syndrome showed increased mitochondrial degradation (PMID: 27640307). Similarly, a reduction in mitochondrial content and aberrant mitochondrial morphology were observed in Drosophila harboring this mutation (PMID: 27640307). This variant is absent from the ExAC and gnomAD population databases. Algorithms developed to predict the effect of missense changes on protein function suggest this variant is likely to be deleterious. Analysis of the parental samples was negative for the variant, indicating this variant likely occurred as a de novo event. Based on the available evidence, the p.Arg576Trp variant in ATAD3A is classified as pathogenic change. -
Pathogenic, flagged submission	research	Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine	-	This variant has been identified as de novo in 5 individuals with delayed motor development and hypotonia. Please see PMID: 27640307 for full description. -
Pathogenic, criteria provided, single submitter	clinical testing	Genomics England Pilot Project, Genomics England	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	May 22, 2022	The variant is not observed in the gnomAD v2.1.1 dataset. Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID:27640307). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.72; 3Cnet: 0.85). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000225696). The variant has been previously reported as de novo in at least two similarly affected unrelated individuals (PMID: 27640307). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, no assertion criteria provided	research	University of Washington Center for Mendelian Genomics, University of Washington	May 25, 2017	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 23, 2020	- -

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	research	Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine	Apr 26, 2016	recurrent de novo variant identified in 5 probands -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 17, 2022	Published functional studies demonstrate a damaging effect including reduction in mitochondria density and number in motor neurons and muscle, as well as an increase in mitophagic vesicles (Harel et al., 2016); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 33146414, 27640307, 28327206, 31019026) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.51
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.33	.;T;.;T
Eigen	Benign	0.019
Eigen_PC	Benign	-0.18
FATHMM_MKL	Benign	0.63	D
LIST_S2	Uncertain	0.87	D;D;D;D
M_CAP	Pathogenic	0.35	D
MetaRNN	Pathogenic	0.94	D;D;D;D
MetaSVM	Uncertain	0.61	D
MutationAssessor	Pathogenic	3.1	.;M;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-7.1	D;D;D;D
REVEL	Pathogenic	0.72
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	.;D;.;.
Vest4		0.97
MutPred		0.76		.;Loss of disorder (P = 0.0398);.;.;
MVP		0.93
MPC		1.4
ClinPred		0.99	D
GERP RS		2.4
Varity_R		0.73
gMVP		0.90

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs1057517686; hg19: chr1-1464679;