Genetic Variant NM_001170535.3:c.155C>T (chr1-1512423-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001170535.3(ATAD3A):c.155C>T(p.Pro52Leu) variant causes a missense change. 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)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

ATAD3A
NM_001170535.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.91

Publications

0 publications found

Variant links:

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

ATAD3A links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ATAD3A	NM_001170535.3	MANE Select	c.155C>T	p.Pro52Leu	missense	Exon 1 of 16	NP_001164006.1	Q9NVI7-2
ATAD3A	NM_018188.5		c.155C>T	p.Pro52Leu	missense	Exon 1 of 16	NP_060658.3
ATAD3A	NM_001170536.3		c.-300C>T		upstream_gene	N/A	NP_001164007.1	Q9NVI7-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ATAD3A	ENST00000378756.8	TSL:1 MANE Select	c.155C>T	p.Pro52Leu	missense	Exon 1 of 16	ENSP00000368031.3	Q9NVI7-2
ATAD3A	ENST00000378755.9	TSL:2	c.155C>T	p.Pro52Leu	missense	Exon 1 of 16	ENSP00000368030.5	Q9NVI7-1
ATAD3A	ENST00000936382.1		c.155C>T	p.Pro52Leu	missense	Exon 1 of 16	ENSP00000606441.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1080868

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

512534

African (AFR)

AF:

0.00

AC:

AN:

21968

American (AMR)

AF:

0.00

AC:

AN:

7688

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

13278

East Asian (EAS)

AF:

0.00

AC:

AN:

24586

South Asian (SAS)

AF:

0.00

AC:

AN:

20258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2816

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

914470

Other (OTH)

AF:

0.00

AC:

AN:

42386

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Harel-Yoon syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Uncertain

-0.020

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.30

Eigen

Pathogenic

0.71

Eigen_PC

Uncertain

0.61

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.97

M_CAP

Pathogenic

0.83

MetaRNN

Uncertain

0.52

MetaSVM

Pathogenic

0.83

MutationAssessor

Pathogenic

3.0

PhyloP100

6.9

PrimateAI

Pathogenic

0.94

PROVEAN

Uncertain

-3.8

REVEL

Uncertain

0.44

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.0030

Polyphen

1.0

Vest4

0.55

MutPred

0.27

Gain of helix (P = 0.0325)

MVP

0.97

MPC

1.1

ClinPred

1.0

GERP RS

3.9

PromoterAI

0.074

Neutral

(source)

Varity_R

0.58

gMVP

0.74

Mutation Taster

=33/67

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over