18-46087222-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2PP2PP3_StrongPP5

The NM_004046.6(ATP5F1A):​c.962A>G​(p.Tyr321Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

Frequency

Genomes: not found (cov: 33)

Consequence

ATP5F1A
NM_004046.6 missense

Scores

16
2
1

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 7.93
Variant links:
Genes affected
ATP5F1A (HGNC:823): (ATP synthase F1 subunit alpha) This gene encodes a subunit of mitochondrial ATP synthase. Mitochondrial ATP synthase catalyzes ATP synthesis, using 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 alpha subunit of the catalytic core. Alternatively spliced transcript variants encoding the different isoforms have been identified. Pseudogenes of this gene are located on chromosomes 9, 2, and 16. [provided by RefSeq, Mar 2012]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), ATP5F1A. . Gene score misZ 2.437 (greater than the threshold 3.09). Trascript score misZ 3.1515 (greater than threshold 3.09). GenCC has associacion of gene with mitochondrial complex V (ATP synthase) deficiency nuclear type 4B, mitochondrial proton-transporting ATP synthase complex deficiency, combined oxidative phosphorylation deficiency 22, mitochondrial complex V (ATP synthase) deficiency, nuclear type 4A, mitochondrial disease.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.945
PP5
Variant 18-46087222-T-C is Pathogenic according to our data. Variant chr18-46087222-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 156426.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ATP5F1ANM_004046.6 linkuse as main transcriptc.962A>G p.Tyr321Cys missense_variant 8/12 ENST00000398752.11 NP_004037.1 P25705-1V9HW26

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ATP5F1AENST00000398752.11 linkuse as main transcriptc.962A>G p.Tyr321Cys missense_variant 8/121 NM_004046.6 ENSP00000381736.5 P25705-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
33
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

Combined oxidative phosphorylation deficiency 22 Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMMay 07, 2013- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.99
BayesDel_addAF
Pathogenic
0.44
D
BayesDel_noAF
Pathogenic
0.40
CADD
Pathogenic
32
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.88
D;.;D;.
Eigen
Pathogenic
0.99
Eigen_PC
Pathogenic
0.84
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
0.98
.;D;D;D
M_CAP
Pathogenic
0.53
D
MetaRNN
Pathogenic
0.95
D;D;D;D
MetaSVM
Pathogenic
0.99
D
MutationAssessor
Pathogenic
3.9
H;.;H;.
PrimateAI
Pathogenic
0.88
D
PROVEAN
Pathogenic
-8.2
D;.;D;.
REVEL
Pathogenic
0.91
Sift
Uncertain
0.0040
D;.;D;.
Sift4G
Pathogenic
0.0
D;D;D;D
Polyphen
1.0
D;.;D;.
Vest4
0.90
MutPred
0.72
Loss of phosphorylation at Y321 (P = 0.0554);.;Loss of phosphorylation at Y321 (P = 0.0554);.;
MVP
0.92
MPC
2.7
ClinPred
1.0
D
GERP RS
4.7
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.94
gMVP
0.97

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs587777788; hg19: chr18-43667188; API