Genetic Variant NM_001170535.3:c.128C>A (chr1-1512396-C-A) – 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.128C>A(p.Pro43His) 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: 4.12

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.128C>A	p.Pro43His	missense	Exon 1 of 16	NP_001164006.1	Q9NVI7-2
ATAD3A	NM_018188.5		c.128C>A	p.Pro43His	missense	Exon 1 of 16	NP_060658.3
ATAD3A	NM_001170536.3		c.-327C>A		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.128C>A	p.Pro43His	missense	Exon 1 of 16	ENSP00000368031.3	Q9NVI7-2
ATAD3A	ENST00000378755.9	TSL:2	c.128C>A	p.Pro43His	missense	Exon 1 of 16	ENSP00000368030.5	Q9NVI7-1
ATAD3A	ENST00000936382.1		c.128C>A	p.Pro43His	missense	Exon 1 of 16	ENSP00000606441.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

1087334

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

516480

African (AFR)

AF:

0.00

AC:

AN:

22216

American (AMR)

AF:

0.00

AC:

AN:

7874

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

13566

East Asian (EAS)

AF:

0.00

AC:

AN:

25046

South Asian (SAS)

AF:

0.00

AC:

AN:

20110

European-Finnish (FIN)

AF:

0.00

AC:

AN:

34120

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2858

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

918792

Other (OTH)

AF:

0.00

AC:

AN:

42752

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Benign

-0.090

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.0079

Eigen

Uncertain

0.51

Eigen_PC

Uncertain

0.44

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.77

M_CAP

Pathogenic

0.83

MetaRNN

Uncertain

0.47

MetaSVM

Uncertain

0.73

MutationAssessor

Uncertain

2.6

PhyloP100

4.1

PrimateAI

Pathogenic

0.90

PROVEAN

Benign

-1.8

REVEL

Benign

0.29

Sift

Benign

0.070

Sift4G

Uncertain

0.046

Polyphen

1.0

Vest4

0.34

MutPred

0.21

Loss of glycosylation at P43 (P = 0.0471)

MVP

0.95

MPC

1.2

ClinPred

0.96

GERP RS

3.9

PromoterAI

-0.023

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.37

gMVP

0.48

Mutation Taster

=59/41

polymorphism

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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