chr10-87754800-C-T

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. 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
• Publications: 3 publications found

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]

ATAD1 Gene-Disease associations (from GenCC):

• hyperekplexia 4

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• hereditary hyperekplexia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.23122153).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001321967.2. 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
	ATAD1	NM_001321967.2	MANE Select	c.973G>A	p.Glu325Lys	missense	Exon 10 of 10	NP_001308896.1	Q8NBU5-1
	ATAD1	NM_032810.4		c.973G>A	p.Glu325Lys	missense	Exon 10 of 10	NP_116199.2
	ATAD1	NM_001321968.2		c.883G>A	p.Glu295Lys	missense	Exon 9 of 9	NP_001308897.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATAD1	ENST00000680024.1	MANE Select	c.973G>A	p.Glu325Lys	missense	Exon 10 of 10	ENSP00000506333.1	Q8NBU5-1
	ATAD1	ENST00000328142.3	TSL:1	c.973G>A	p.Glu325Lys	missense	Exon 9 of 9	ENSP00000339016.2	Q8NBU5-1
	ATAD1	ENST00000944904.1		c.997G>A	p.Glu333Lys	missense	Exon 11 of 11	ENSP00000614963.1

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

GnomAD2 exomes AF: 0.0000120 AC: 3 AN: 250436 AF XY: 0.00000739

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 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

African (AFR) AF: 0.0000299 AC: 1 AN: 33446

American (AMR) AF: 0.0000224 AC: 1 AN: 44596

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26068

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39604

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86096

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53344

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5746

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1110796

Other (OTH) AF: 0.00 AC: 0 AN: 60296

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

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000241 AC: 1 AN: 41562

American (AMR) AF: 0.00 AC: 0 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10592

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2116

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0000434 Hom.: 0

ExAC AF: 0.00000824 AC: 1

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

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
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
MetaSVM	Uncertain	0.62	D
MutationAssessor	Benign	1.1	L
PhyloP100		5.1
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-1.1	N
REVEL	Uncertain	0.48
Sift	Benign	0.31	T
Sift4G	Benign	0.32	T
Polyphen		0.36	B
Vest4		0.32
MutPred		0.35		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
Mutation Taster		=21/79	disease causing

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

Other links and lift over

dbSNP: rs545576634; hg19: chr10-89514557;