1-1512338-C-A

Variant names:

• chr1-1512338-C-A
• rs1641221082
• NM_001170535.3:c.70C>A

Variant summary

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

The NM_001170535.3(ATAD3A):​c.70C>A​(p.Pro24Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000101 in 1,089,088 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P24S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: ATAD3A NM_001170535.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.79
• Publications: 0 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: AR, AD, SD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: G2P, Ambry Genetics, Illumina, Labcorp Genetics (formerly Invitae)
• pontocerebellar hypoplasia, hypotonia, and respiratory insufficiency syndrome, neonatal lethal

  Inheritance: AR Classification: MODERATE Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001170535.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATAD3A	NM_001170535.3	MANE Select	c.70C>A	p.Pro24Thr	missense	Exon 1 of 16	NP_001164006.1	Q9NVI7-2
	ATAD3A	NM_018188.5		c.70C>A	p.Pro24Thr	missense	Exon 1 of 16	NP_060658.3
	ATAD3A	NM_001170536.3		c.-385C>A		upstream_gene	N/A	NP_001164007.1	Q9NVI7-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATAD3A	ENST00000378756.8	TSL:1 MANE Select	c.70C>A	p.Pro24Thr	missense	Exon 1 of 16	ENSP00000368031.3	Q9NVI7-2
	ATAD3A	ENST00000378755.9	TSL:2	c.70C>A	p.Pro24Thr	missense	Exon 1 of 16	ENSP00000368030.5	Q9NVI7-1
	ATAD3A	ENST00000936382.1		c.70C>A	p.Pro24Thr	missense	Exon 1 of 16	ENSP00000606441.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000101 AC: 11 AN: 1089088 Hom.: 0 Cov.: 30 AF XY: 0.0000136 AC XY: 7 AN XY: 516166

African (AFR) AF: 0.00 AC: 0 AN: 22502

American (AMR) AF: 0.00 AC: 0 AN: 8108

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13876

East Asian (EAS) AF: 0.00 AC: 0 AN: 25844

South Asian (SAS) AF: 0.00 AC: 0 AN: 19740

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33842

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2894

European-Non Finnish (NFE) AF: 0.0000109 AC: 10 AN: 919134

Other (OTH) AF: 0.0000232 AC: 1 AN: 43148

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Uncertain	0.040	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0097	T
Eigen	Benign	0.12
Eigen_PC	Benign	0.062
FATHMM_MKL	Benign	0.62	D
LIST_S2	Benign	0.72	T
M_CAP	Pathogenic	0.80	D
MetaRNN	Uncertain	0.44	T
MetaSVM	Uncertain	0.025	D
MutationAssessor	Uncertain	2.5	M
PhyloP100		1.8
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-2.5	D
REVEL	Uncertain	0.41
Sift	Benign	0.20	T
Sift4G	Benign	0.11	T
Polyphen		0.95	P
Vest4		0.17
MutPred		0.17		Gain of phosphorylation at P24 (P = 0.0113)
MVP		0.87
MPC		1.1
ClinPred		0.98	D
GERP RS		2.9
PromoterAI		0.017	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.19
gMVP		0.54
Mutation Taster		=69/31	polymorphism

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: rs1641221082; hg19: chr1-1447718;