1-1512447-A-G

Variant names:

• chr1-1512447-A-G
• rs1028244940
• NM_001170535.3:c.179A>G

Variant summary

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

The NM_001170535.3(ATAD3A):​c.179A>G​(p.Lys60Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000704 in 142,146 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 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. K60L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000070 (0 hom., cov: 29)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ATAD3A NM_001170535.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.36
• 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=0.3201041).

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.179A>G	p.Lys60Arg	missense	Exon 1 of 16	NP_001164006.1	Q9NVI7-2
	ATAD3A	NM_018188.5		c.179A>G	p.Lys60Arg	missense	Exon 1 of 16	NP_060658.3
	ATAD3A	NM_001170536.3		c.-276A>G		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.179A>G	p.Lys60Arg	missense	Exon 1 of 16	ENSP00000368031.3	Q9NVI7-2
	ATAD3A	ENST00000378755.9	TSL:2	c.179A>G	p.Lys60Arg	missense	Exon 1 of 16	ENSP00000368030.5	Q9NVI7-1
	ATAD3A	ENST00000936382.1		c.179A>G	p.Lys60Arg	missense	Exon 1 of 16	ENSP00000606441.1

Frequencies

GnomAD3 genomes AF: 0.00000704 AC: 1 AN: 142146 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.0000266

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1009862 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 476118

African (AFR) AF: 0.00 AC: 0 AN: 19386

American (AMR) AF: 0.00 AC: 0 AN: 5566

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 10736

East Asian (EAS) AF: 0.00 AC: 0 AN: 17938

South Asian (SAS) AF: 0.00 AC: 0 AN: 19630

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 24454

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2436

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 872212

Other (OTH) AF: 0.00 AC: 0 AN: 37504

GnomAD4 genome AF: 0.00000704 AC: 1 AN: 142146 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 69066

African (AFR) AF: 0.0000266 AC: 1 AN: 37658

American (AMR) AF: 0.00 AC: 0 AN: 14422

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3380

East Asian (EAS) AF: 0.00 AC: 0 AN: 4398

South Asian (SAS) AF: 0.00 AC: 0 AN: 4292

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9074

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 284

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 65800

Other (OTH) AF: 0.00 AC: 0 AN: 1954

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	0.0047	T
BayesDel_noAF	Benign	-0.23
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.011	T
Eigen	Benign	-0.091
Eigen_PC	Benign	0.022
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.89	D
M_CAP	Pathogenic	0.87	D
MetaRNN	Benign	0.32	T
MetaSVM	Uncertain	-0.16	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		6.4
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-1.5	N
REVEL	Uncertain	0.33
Sift	Benign	0.056	T
Sift4G	Benign	0.11	T
Polyphen		0.070	B
Vest4		0.12
MutPred		0.28		Loss of glycosylation at K60 (P = 0.0158)
MVP		0.90
MPC		0.29
ClinPred		0.93	D
GERP RS		3.9
PromoterAI		-0.017	Neutral
Varity_R		0.32
gMVP		0.46
Mutation Taster		=76/24	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: rs1028244940; hg19: chr1-1447827; COSMIC: COSV105195725; COSMIC: COSV105195725;