1-1512423-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001170535.3(ATAD3A):c.155C>T(p.Pro52Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ATAD3A NM_001170535.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.91

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATAD3A	NM_001170535.3	c.155C>T	p.Pro52Leu	missense_variant	1/16	ENST00000378756.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATAD3A	ENST00000378756.8	c.155C>T	p.Pro52Leu	missense_variant	1/16	1	NM_001170535.3	P1
ATAD3A	ENST00000378755.9	c.155C>T	p.Pro52Leu	missense_variant	1/16	2
ATAD3A	ENST00000672388.1	n.259C>T		non_coding_transcript_exon_variant	1/14
ATAD3A	ENST00000339113.9	c.41C>T	p.Pro14Leu	missense_variant, NMD_transcript_variant	1/17	2

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1080868 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 512534

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 29

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Harel-Yoon syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Department of Human Genetics, Hannover Medical School

Aug 25, 2022

The variant is not yet known in the ClinVar and LOVD variant databases or in the literature. It is also not listed in the population database gnomAD. This missense variant affects an evolutionarily moderately conserved amino acid. The physicochemical difference between the original (proline) and the newly evolved amino acid (leucine) is moderate. An in silico analysis regarding the clinical relevance of the change did not yield a clear result. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
Cadd	Pathogenic	32
Dann	Uncertain	1.0
Eigen	Pathogenic	0.71
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Pathogenic	0.83	D
MetaRNN	Uncertain	0.52	D;D
MetaSVM	Pathogenic	0.83	D
MutationAssessor	Pathogenic	3.0	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.94	D
PROVEAN	Uncertain	-3.8	D;D
REVEL	Uncertain	0.44
Sift	Uncertain	0.0020	D;D
Sift4G	Uncertain	0.0030	D;D
Polyphen		1.0	.;D
Vest4		0.55
MutPred		0.27		Gain of helix (P = 0.0325);Gain of helix (P = 0.0325);
MVP		0.97
MPC		1.1
ClinPred		1.0	D
GERP RS		3.9
Varity_R		0.58
gMVP		0.74

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-1447803;