1-1512418-C-G

Position:

• chr1-1512418-C-G

Variant summary

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

The NM_001170535.3(ATAD3A):​c.150C>G​(p.Phe50Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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)
• Consequence: ATAD3A NM_001170535.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.819

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	Protein	UniProt
ATAD3A	NM_001170535.3	c.150C>G	p.Phe50Leu	missense_variant	1/16	ENST00000378756.8	NP_001164006.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATAD3A	ENST00000378756.8	c.150C>G	p.Phe50Leu	missense_variant	1/16	1	NM_001170535.3	ENSP00000368031	P1
ATAD3A	ENST00000378755.9	c.150C>G	p.Phe50Leu	missense_variant	1/16	2		ENSP00000368030
ATAD3A	ENST00000672388.1	n.254C>G		non_coding_transcript_exon_variant	1/14
ATAD3A	ENST00000339113.9	c.36C>G	p.Phe12Leu	missense_variant, NMD_transcript_variant	1/17	2		ENSP00000339421

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome Cov.: 31

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

Hadassah Hebrew University Medical Center

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.16	.;T
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Uncertain	0.88	D;D
M_CAP	Pathogenic	0.77	D
MetaRNN	Uncertain	0.59	D;D
MetaSVM	Uncertain	0.35	D
MutationAssessor	Uncertain	2.8	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.96	D
PROVEAN	Pathogenic	-5.0	D;D
REVEL	Uncertain	0.44
Sift	Benign	0.054	T;T
Sift4G	Uncertain	0.0060	D;D
Polyphen		1.0	.;D
Vest4		0.56
MutPred		0.33		Gain of MoRF binding (P = 0.1411);Gain of MoRF binding (P = 0.1411);
MVP		0.91
MPC		0.54
ClinPred		0.99	D
GERP RS		1.9
Varity_R		0.56
gMVP		0.76

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

LitVar

Other links and lift over

dbSNP: rs1641223867; hg19: chr1-1447798;