rs1057517687

Variant names:

• chr1-1512426-C-T
• rs1057517687
• NM_001170535.3:c.158C>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP5

The NM_001170535.3(ATAD3A):​c.158C>T​(p.Thr53Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000371 in 1,079,372 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 0.0000037 (0 hom.)
• Consequence: ATAD3A NM_001170535.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:2
• Conservation: PhyloP100: 5.23
• Publications: 5 publications found

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 Gene-Disease associations (from GenCC):

• Harel-Yoon syndrome

  Inheritance: AD, AR, SD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Illumina, G2P
• pontocerebellar hypoplasia, hypotonia, and respiratory insufficiency syndrome, neonatal lethal

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, PanelApp Australia

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-1512426-C-T is Pathogenic according to our data. Variant chr1-1512426-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 225697.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATAD3A	NM_001170535.3	c.158C>T	p.Thr53Ile	missense_variant	Exon 1 of 16	ENST00000378756.8	NP_001164006.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATAD3A	ENST00000378756.8	c.158C>T	p.Thr53Ile	missense_variant	Exon 1 of 16	1	NM_001170535.3	ENSP00000368031.3

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome AF: 0.00000371 AC: 4 AN: 1079372 Hom.: 0 Cov.: 31 AF XY: 0.00000391 AC XY: 2 AN XY: 511802

African (AFR) AF: 0.00 AC: 0 AN: 21902

American (AMR) AF: 0.00 AC: 0 AN: 7642

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13214

East Asian (EAS) AF: 0.00 AC: 0 AN: 24450

South Asian (SAS) AF: 0.00 AC: 0 AN: 20254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33200

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2810

European-Non Finnish (NFE) AF: 0.00000438 AC: 4 AN: 913608

Other (OTH) AF: 0.00 AC: 0 AN: 42292

GnomAD4 genome Cov.: 29

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Harel-Yoon syndrome Pathogenic:1

Nov 29, 2016

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Pathogenic:1

Jul 01, 2017

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Uncertain:1

Apr 26, 2016

Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

homozygous variant identified in siblings -

Pontocerebellar hypoplasia, hypotonia, and respiratory insufficiency syndrome, neonatal lethal Uncertain:1

Apr 04, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.060
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.19	.;T
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Pathogenic	0.85	D
MetaRNN	Uncertain	0.71	D;D
MetaSVM	Uncertain	0.68	D
MutationAssessor	Uncertain	2.3	M;M
PhyloP100		5.2
PrimateAI	Pathogenic	0.95	D
PROVEAN	Uncertain	-3.2	D;D
REVEL	Uncertain	0.56
Sift	Uncertain	0.0030	D;D
Sift4G	Benign	0.077	T;D
Polyphen		1.0	.;D
Vest4		0.54
MutPred		0.15		Loss of phosphorylation at T53 (P = 0.0203);Loss of phosphorylation at T53 (P = 0.0203);
MVP		0.94
MPC		1.1
ClinPred		0.99	D
GERP RS		3.9
PromoterAI		0.082	Neutral
Varity_R		0.62
gMVP		0.57
Mutation Taster		=3/97	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1057517687; hg19: chr1-1447806;