rs867410737

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2PP3_StrongPP5

The NM_001687.5(ATP5F1D):c.245C>T(p.Pro82Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000215 in 1,393,054 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000022 ( 0 hom. )

Consequence

ATP5F1D
NM_001687.5 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:2

Conservation

PhyloP100: 7.51

Publications

2 publications found

Variant links:

Genes affected

ATP5F1D (HGNC:837): (ATP synthase F1 subunit delta) This gene encodes a subunit of mitochondrial ATP synthase. Mitochondrial ATP synthase catalyzes ATP synthesis, utilizing an electrochemical gradient of protons across the inner membrane during oxidative phosphorylation. ATP synthase is composed of two linked multi-subunit complexes: the soluble catalytic core, F1, and the membrane-spanning component, Fo, comprising the proton channel. The catalytic portion of mitochondrial ATP synthase consists of 5 different subunits (alpha, beta, gamma, delta, and epsilon) assembled with a stoichiometry of 3 alpha, 3 beta, and a single representative of the other 3. The proton channel consists of three main subunits (a, b, c). This gene encodes the delta subunit of the catalytic core. Alternatively spliced transcript variants encoding the same isoform have been identified. [provided by RefSeq, Jul 2008]

ATP5F1D Gene-Disease associations (from GenCC):

mitochondrial complex V (ATP synthase) deficiency, nuclear type 5
Inheritance: AR Classification: STRONG, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae)
mitochondrial proton-transporting ATP synthase complex deficiency
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ATP5F1D links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.98

PP5

Variant 19-1242559-C-T is Pathogenic according to our data. Variant chr19-1242559-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 453296.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP5F1D	NM_001687.5 link	c.245C>T	p.Pro82Leu	missense_variant	Exon 2 of 4	ENST00000215375.7	NP_001678.1	P30049
ATP5F1D	NM_001001975.2 link	c.245C>T	p.Pro82Leu	missense_variant	Exon 2 of 5		NP_001001975.1	P30049

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP5F1D	ENST00000215375.7 link	c.245C>T	p.Pro82Leu	missense_variant	Exon 2 of 4	1	NM_001687.5	ENSP00000215375.1		P30049

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000674

AC:

AN:

148408

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000418

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:

0.00000215

AC:

AN:

1393054

Hom.:

Cov.:

AF XY:

0.00000291

AC XY:

AN XY:

686518

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31408

American (AMR)

AF:

0.0000282

AC:

AN:

35456

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25108

East Asian (EAS)

AF:

0.00

AC:

AN:

35430

South Asian (SAS)

AF:

0.00

AC:

AN:

78640

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47934

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5372

European-Non Finnish (NFE)

AF:

0.00000186

AC:

AN:

1075972

Other (OTH)

AF:

0.00

AC:

AN:

57734

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.442

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Mitochondrial complex V (ATP synthase) deficiency, nuclear type 5

Pathogenic:1

Sep 14, 2018

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Decreased activity of mitochondrial ATP synthase complex

Pathogenic:1

Jun 01, 2017

Undiagnosed Diseases Network, NIH

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

Pathogenicity of this variant was established through patient-specific functional assays including untargeted serum metabolomics, western blot, Blue Native PAGE, Seahorse energetics, and electron microscopy of iPSC-derived cardiomyocytes which were all consistent with impaired ATPase function. Additional evidence for gene- and variant-specific pathogenicity included in vivo transgenic Drosophila studies with attempted rescue. This individual has been reported in PMID:29478781 (subject 1). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.93

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Pathogenic

0.27

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.58

D;D;D

Eigen

Pathogenic

0.83

Eigen_PC

Uncertain

0.66

FATHMM_MKL

Uncertain

0.92

LIST_S2

Pathogenic

0.99

.;.;D

M_CAP

Pathogenic

0.35

MetaRNN

Pathogenic

0.98

D;D;D

MetaSVM

Uncertain

0.76

MutationAssessor

Pathogenic

3.9

H;H;H

PhyloP100

7.5

PrimateAI

Uncertain

0.73

PROVEAN

Pathogenic

-9.8

D;D;.

REVEL

Uncertain

0.58

Sift

Pathogenic

0.0

D;D;.

Sift4G

Uncertain

0.0060

D;D;D

Polyphen

1.0

D;D;D

Vest4

0.90

MutPred

0.81

Gain of relative solvent accessibility (P = 0.1894);Gain of relative solvent accessibility (P = 0.1894);Gain of relative solvent accessibility (P = 0.1894);

MVP

0.80

MPC

1.2

ClinPred

1.0

GERP RS

5.1

PromoterAI

0.0014

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.86

gMVP

0.83

Mutation Taster

=4/96

disease causing (ClinVar)

(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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rs867410737

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over