8-123322975-C-A

Variant names:

• chr8-123322975-C-A
• rs111422836
• NM_014109.4:c.4094G>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_014109.4(ATAD2):​c.4094G>T​(p.Arg1365Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign 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. R1365Q) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ATAD2 NM_014109.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0220
• Publications: 2 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2755882).

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.4094G>T	p.Arg1365Leu	missense	Exon 27 of 28	NP_054828.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATAD2	ENST00000287394.10	TSL:1 MANE Select	c.4094G>T	p.Arg1365Leu	missense	Exon 27 of 28	ENSP00000287394.5	Q6PL18-1
	ATAD2	ENST00000521903.5	TSL:1	c.2048G>T	p.Arg683Leu	missense	Exon 28 of 29	ENSP00000429213.1	A0A0B4J211
	ATAD2	ENST00000519124.5	TSL:1	n.*3904G>T		non_coding_transcript_exon	Exon 27 of 28	ENSP00000429617.1	E5RHW7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	0.011	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	15
DANN	Uncertain	0.99
DEOGEN2	Benign	0.29	T
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.36
FATHMM_MKL	Benign	0.59	D
LIST_S2	Benign	0.67	T
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.28	T
MetaSVM	Uncertain	-0.23	T
MutationAssessor	Benign	2.0	M
PhyloP100		-0.022
PrimateAI	Benign	0.31	T
PROVEAN	Pathogenic	-4.4	D
REVEL	Benign	0.22
Sift	Benign	0.047	D
Sift4G	Benign	0.13	T
Polyphen		0.61	P
Vest4		0.28
MutPred		0.34		Gain of helix (P = 0.0349)
MVP		0.47
MPC		0.39
ClinPred		0.85	D
GERP RS		3.2
Varity_R		0.099
gMVP		0.29
Mutation Taster		=93/7	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: rs111422836; hg19: chr8-124335215;