Genetic Variant ATAD2:p.Met1379Val (chr8-123321172-T-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_014109.4(ATAD2):c.4135A>G(p.Met1379Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,456,488 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

ATAD2
NM_014109.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.79

Variant links:

Genes affected

ATAD2 (HGNC:30123): (ATPase family AAA domain containing 2) A large family of ATPases has been described, whose key feature is that they share a conserved region of about 220 amino acids that contains an ATP-binding site. The proteins that belong to this family either contain one or two AAA (ATPases Associated with diverse cellular Activities) domains. AAA family proteins often perform chaperone-like functions that assist in the assembly, operation, or disassembly of protein complexes. The protein encoded by this gene contains two AAA domains, as well as a bromodomain. [provided by RefSeq, Jul 2008]

ATAD2 links:

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ACMG classification

Classification made for transcript

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 rank	MANE	Protein	UniProt
ATAD2	NM_014109.4 link	c.4135A>G	p.Met1379Val	missense_variant	Exon 28 of 28	ENST00000287394.10	NP_054828.2	Q6PL18-1A0A024R9G7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATAD2	ENST00000287394.10 link	c.4135A>G	p.Met1379Val	missense_variant	Exon 28 of 28	1	NM_014109.4	ENSP00000287394.5		Q6PL18-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1456488

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

724708

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000235

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Asia WGS

AF:

0.000289

AC:

AN:

3470

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 29, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.4135A>G (p.M1379V) alteration is located in exon 28 (coding exon 28) of the ATAD2 gene. This alteration results from a A to G substitution at nucleotide position 4135, causing the methionine (M) at amino acid position 1379 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.40

BayesDel_addAF

Pathogenic

0.22

BayesDel_noAF

Uncertain

0.080

CADD

Benign

DANN

Benign

0.93

DEOGEN2

Benign

0.098

T;.

Eigen

Benign

-0.068

Eigen_PC

Benign

0.092

FATHMM_MKL

Uncertain

0.80

LIST_S2

Benign

0.64

T;T

M_CAP

Uncertain

0.10

MetaRNN

Uncertain

0.50

T;T

MetaSVM

Uncertain

0.19

MutationAssessor

Benign

2.0

M;.

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-2.0

N;N

REVEL

Uncertain

0.31

Sift

Uncertain

0.0090

D;D

Sift4G

Uncertain

0.044

D;T

Polyphen

0.0060

B;.

Vest4

0.56

MutPred

0.37

Gain of loop (P = 0.0045);.;

MVP

0.95

MPC

0.24

ClinPred

0.38

GERP RS

5.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.28

gMVP

0.44

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.14

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over