Genetic Variant ATAD1:p.His357Gln (chr10-87754702-A-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001321967.2(ATAD1):c.1071T>A(p.His357Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,878 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. H357H) has been classified as Benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

ATAD1
NM_001321967.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.725

Publications

0 publications found

Variant links:

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

ATAD1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.112307906).

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ATAD1	NM_001321967.2	MANE Select	c.1071T>A	p.His357Gln	missense	Exon 10 of 10	NP_001308896.1	Q8NBU5-1
ATAD1	NM_032810.4		c.1071T>A	p.His357Gln	missense	Exon 10 of 10	NP_116199.2
ATAD1	NM_001321968.2		c.981T>A	p.His327Gln	missense	Exon 9 of 9	NP_001308897.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ATAD1	ENST00000680024.1	MANE Select	c.1071T>A	p.His357Gln	missense	Exon 10 of 10	ENSP00000506333.1	Q8NBU5-1
ATAD1	ENST00000328142.3	TSL:1	c.1071T>A	p.His357Gln	missense	Exon 9 of 9	ENSP00000339016.2	Q8NBU5-1
ATAD1	ENST00000944904.1		c.1095T>A	p.His365Gln	missense	Exon 11 of 11	ENSP00000614963.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000399

AC:

AN:

250874

AF XY:

0.00000737

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460878

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726742

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33446

American (AMR)

AF:

0.00

AC:

AN:

44708

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26112

East Asian (EAS)

AF:

0.00

AC:

AN:

39636

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86218

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53388

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5532

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111520

Other (OTH)

AF:

0.00

AC:

AN:

60318

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

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

Benign

0.10

BayesDel_addAF

Benign

-0.025

BayesDel_noAF

Benign

-0.17

CADD

Benign

8.5

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.31

Eigen

Benign

-1.1

Eigen_PC

Benign

-0.92

FATHMM_MKL

Benign

0.30

M_CAP

Benign

0.068

MetaRNN

Benign

0.11

MetaSVM

Benign

-0.55

MutationAssessor

Benign

1.4

PhyloP100

-0.72

PrimateAI

Uncertain

0.70

PROVEAN

Benign

-0.10

REVEL

Uncertain

0.43

Sift

Benign

0.20

Sift4G

Benign

0.52

Polyphen

0.0

Vest4

0.27

MutPred

0.44

Loss of catalytic residue at D361 (P = 0.094)

MVP

0.63

MPC

0.58

ClinPred

0.069

GERP RS

0.36

Varity_R

0.070

gMVP

0.48

Mutation Taster

=88/12

polymorphism

(source)

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

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