Genetic Variant ATAD2:p.Arg1367Ser (chr8-123322970-G-T) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_014109.4(ATAD2):c.4099C>A(p.Arg1367Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,484 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1367C) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

ATAD2
NM_014109.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.34

Publications

0 publications found

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 was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.866

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014109.4. 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
	ATAD2	NM_014109.4	MANE Select	c.4099C>A	p.Arg1367Ser	missense	Exon 27 of 28	NP_054828.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ATAD2	ENST00000287394.10	TSL:1 MANE Select	c.4099C>A	p.Arg1367Ser	missense	Exon 27 of 28	ENSP00000287394.5	Q6PL18-1
ATAD2	ENST00000521903.5	TSL:1	c.2053C>A	p.Arg685Ser	missense	Exon 28 of 29	ENSP00000429213.1	A0A0B4J211
ATAD2	ENST00000519124.5	TSL:1	n.*3909C>A		non_coding_transcript_exon	Exon 27 of 28	ENSP00000429617.1	E5RHW7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461484

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727028

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33472

American (AMR)

AF:

0.00

AC:

AN:

44686

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26126

East Asian (EAS)

AF:

0.00

AC:

AN:

39656

South Asian (SAS)

AF:

0.00

AC:

AN:

86198

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53396

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111816

Other (OTH)

AF:

0.00

AC:

AN:

60372

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.91

BayesDel_addAF

Pathogenic

0.54

BayesDel_noAF

Pathogenic

0.54

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.32

Eigen

Pathogenic

0.84

Eigen_PC

Pathogenic

0.82

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Pathogenic

0.98

M_CAP

Uncertain

0.27

MetaRNN

Pathogenic

0.87

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

3.2

PhyloP100

7.3

PrimateAI

Uncertain

0.52

PROVEAN

Uncertain

-4.1

REVEL

Pathogenic

0.83

Sift

Uncertain

0.011

Sift4G

Uncertain

0.011

Polyphen

1.0

Vest4

0.92

MutPred

0.50

Gain of helix (P = 0.0078)

MVP

0.96

MPC

0.92

ClinPred

0.99

GERP RS

5.7

Varity_R

0.40

gMVP

0.71

Mutation Taster

=65/35

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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