NM_001170535.3:c.131A>G

Variant names:

• chr1-1512399-A-G
• rs995479116
• NM_001170535.3:c.131A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001170535.3(ATAD3A):​c.131A>G​(p.Lys44Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000154 in 1,235,740 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: 𝑓 0.0000066 (0 hom., cov: 29)
  • Exomes 𝑓: 0.000017 (0 hom.)
• Consequence: ATAD3A NM_001170535.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.20
• 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.26248944).

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.131A>G	p.Lys44Arg	missense	Exon 1 of 16	NP_001164006.1	Q9NVI7-2
	ATAD3A	NM_018188.5		c.131A>G	p.Lys44Arg	missense	Exon 1 of 16	NP_060658.3
	ATAD3A	NM_001170536.3		c.-324A>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.131A>G	p.Lys44Arg	missense	Exon 1 of 16	ENSP00000368031.3	Q9NVI7-2
	ATAD3A	ENST00000378755.9	TSL:2	c.131A>G	p.Lys44Arg	missense	Exon 1 of 16	ENSP00000368030.5	Q9NVI7-1
	ATAD3A	ENST00000936382.1		c.131A>G	p.Lys44Arg	missense	Exon 1 of 16	ENSP00000606441.1

Frequencies

GnomAD3 genomes AF: 0.00000665 AC: 1 AN: 150454 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.00

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: 0.0000148

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000166 AC: 18 AN: 1085286 Hom.: 0 Cov.: 31 AF XY: 0.0000155 AC XY: 8 AN XY: 515380

African (AFR) AF: 0.00 AC: 0 AN: 22120

American (AMR) AF: 0.00 AC: 0 AN: 7824

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13444

East Asian (EAS) AF: 0.00 AC: 0 AN: 24880

South Asian (SAS) AF: 0.00 AC: 0 AN: 20094

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34040

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2846

European-Non Finnish (NFE) AF: 0.0000196 AC: 18 AN: 917454

Other (OTH) AF: 0.00 AC: 0 AN: 42584

GnomAD4 genome AF: 0.00000665 AC: 1 AN: 150454 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 73422

African (AFR) AF: 0.00 AC: 0 AN: 40844

American (AMR) AF: 0.00 AC: 0 AN: 15152

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3458

East Asian (EAS) AF: 0.00 AC: 0 AN: 5060

South Asian (SAS) AF: 0.00 AC: 0 AN: 4784

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10194

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.0000148 AC: 1 AN: 67664

Other (OTH) AF: 0.00 AC: 0 AN: 2076

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Harel-Yoon syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	0.00029	T
BayesDel_noAF	Benign	-0.24
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0029	T
Eigen	Benign	0.045
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.89	D
M_CAP	Pathogenic	0.71	D
MetaRNN	Benign	0.26	T
MetaSVM	Uncertain	-0.23	T
MutationAssessor	Benign	0.95	L
PhyloP100		6.2
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-0.56	N
REVEL	Benign	0.16
Sift	Benign	0.28	T
Sift4G	Benign	0.63	T
Polyphen		0.98	D
Vest4		0.20
MutPred		0.13		Loss of ubiquitination at K44 (P = 0.0043)
MVP		0.89
MPC		0.95
ClinPred		0.90	D
GERP RS		3.9
PromoterAI		-0.060	Neutral
Varity_R		0.32
gMVP		0.37
Mutation Taster		=66/34	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: rs995479116; hg19: chr1-1447779;