10-87754800-C-T

Variant names:

• chr10-87754800-C-T
• rs545576634
• NM_001321967.2:c.973G>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001321967.2(ATAD1):​c.973G>A​(p.Glu325Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000558 in 1,612,268 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: ATAD1 NM_001321967.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.13

Genes affected

ATAD1 (HGNC:25903): (ATPase family AAA domain containing 1) Predicted to enable ATP binding activity and transmembrane protein dislocase activity. Involved in extraction of mislocalized protein from mitochondrial outer membrane. Located in mitochondrial outer membrane and peroxisomal membrane. Implicated in hyperekplexia 4. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.23122153).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATAD1	NM_001321967.2	c.973G>A	p.Glu325Lys	missense_variant	Exon 10 of 10	ENST00000680024.1	NP_001308896.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATAD1	ENST00000680024.1	c.973G>A	p.Glu325Lys	missense_variant	Exon 10 of 10		NM_001321967.2	ENSP00000506333.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152158 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000120 AC: 3 AN: 250436 Hom.: 0 AF XY: 0.00000739 AC XY: 1 AN XY: 135394

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000291

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000883

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1459992 Hom.: 0 Cov.: 30 AF XY: 0.00000688 AC XY: 5 AN XY: 726226

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152276 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74448

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000434 Hom.: 0

ExAC AF: 0.00000824 AC: 1

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Aug 10, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ClinVar contains an entry for this variant (Variation ID: 1409365). This sequence change replaces glutamic acid with lysine at codon 325 of the ATAD1 protein (p.Glu325Lys). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is present in population databases (rs545576634, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with ATAD1-related conditions. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	0.050
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.28	T;T
Eigen	Benign	-0.073
Eigen_PC	Benign	0.13
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.23	T;T
MetaSVM	Uncertain	0.62	D
MutationAssessor	Benign	1.1	L;L
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-1.1	N;N
REVEL	Uncertain	0.48
Sift	Benign	0.31	T;T
Sift4G	Benign	0.32	T;T
Polyphen		0.36	B;B
Vest4		0.32
MutPred		0.35		Gain of ubiquitination at E325 (P = 0.0048);Gain of ubiquitination at E325 (P = 0.0048);
MVP		0.82
MPC		0.65
ClinPred		0.45	T
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.18
gMVP		0.47

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

LitVar

Other links and lift over

dbSNP: rs545576634; hg19: chr10-89514557;