NM_001170535.3:c.191A>C

Variant names:

• chr1-1512459-A-C
• rs953298933
• NM_001170535.3:c.191A>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001170535.3(ATAD3A):​c.191A>C​(p.Glu64Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000384 in 1,042,564 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 0.0000038 (0 hom.)
• Consequence: ATAD3A NM_001170535.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.11
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.42349762).

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.191A>C	p.Glu64Ala	missense	Exon 1 of 16	NP_001164006.1	Q9NVI7-2
	ATAD3A	NM_018188.5		c.191A>C	p.Glu64Ala	missense	Exon 1 of 16	NP_060658.3
	ATAD3A	NM_001170536.3		c.-264A>C		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.191A>C	p.Glu64Ala	missense	Exon 1 of 16	ENSP00000368031.3	Q9NVI7-2
	ATAD3A	ENST00000378755.9	TSL:2	c.191A>C	p.Glu64Ala	missense	Exon 1 of 16	ENSP00000368030.5	Q9NVI7-1
	ATAD3A	ENST00000936382.1		c.191A>C	p.Glu64Ala	missense	Exon 1 of 16	ENSP00000606441.1

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome AF: 0.00000384 AC: 4 AN: 1042564 Hom.: 0 Cov.: 31 AF XY: 0.00000406 AC XY: 2 AN XY: 493076

African (AFR) AF: 0.00 AC: 0 AN: 19628

American (AMR) AF: 0.00 AC: 0 AN: 6210

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 11908

East Asian (EAS) AF: 0.00 AC: 0 AN: 19294

South Asian (SAS) AF: 0.00 AC: 0 AN: 21832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 28424

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2584

European-Non Finnish (NFE) AF: 0.00000448 AC: 4 AN: 893014

Other (OTH) AF: 0.00 AC: 0 AN: 39670

GnomAD4 genome Cov.: 29

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.48
BayesDel_addAF	Uncertain	0.059	T
BayesDel_noAF	Benign	-0.15
CADD	Pathogenic	31
DANN	Uncertain	0.99
DEOGEN2	Benign	0.13	T
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.72	D
MetaRNN	Benign	0.42	T
MetaSVM	Uncertain	0.56	D
MutationAssessor	Uncertain	2.1	M
PhyloP100		8.1
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-4.4	D
REVEL	Uncertain	0.34
Sift	Benign	0.13	T
Sift4G	Benign	0.084	T
Polyphen		0.99	D
Vest4		0.30
MutPred		0.18		Gain of MoRF binding (P = 0.0214)
MVP		0.95
MPC		0.95
ClinPred		0.99	D
GERP RS		3.9
PromoterAI		0.033	Neutral
Varity_R		0.69
gMVP		0.66
Mutation Taster		=44/56	disease causing

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: rs953298933; hg19: chr1-1447839;