17-75039219-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_006356.3(ATP5PD):​c.344A>C​(p.Tyr115Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Consequence

ATP5PD
NM_006356.3 missense

Scores

5
9
5

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.41
Variant links:
Genes affected
ATP5PD (HGNC:845): (ATP synthase peripheral stalk subunit d) Mitochondrial ATP synthase catalyzes ATP synthesis, utilizing an electrochemical gradient of protons across the inner membrane during oxidative phosphorylation. It is composed of two linked multi-subunit complexes: the soluble catalytic core, F1, and the membrane-spanning component, Fo, which comprises the proton channel. The F1 complex consists of 5 different subunits (alpha, beta, gamma, delta, and epsilon) assembled in a ratio of 3 alpha, 3 beta, and a single representative of the other 3. The Fo seems to have nine subunits (a, b, c, d, e, f, g, F6 and 8). This gene encodes the d subunit of the Fo complex. Alternatively spliced transcript variants encoding different isoforms have been identified for this gene. In addition, three pseudogenes are located on chromosomes 9, 12 and 15. [provided by RefSeq, Jun 2010]
KCTD2 (HGNC:21294): (potassium channel tetramerization domain containing 2) Predicted to enable cullin family protein binding activity. Predicted to be involved in proteasome-mediated ubiquitin-dependent protein catabolic process. Predicted to be part of Cul3-RING ubiquitin ligase complex. Predicted to be active in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.875

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ATP5PDNM_006356.3 linkc.344A>C p.Tyr115Ser missense_variant Exon 5 of 6 ENST00000301587.9 NP_006347.1 O75947-1A0PJH2
ATP5PDNM_001003785.2 linkc.272A>C p.Tyr91Ser missense_variant Exon 4 of 5 NP_001003785.1 O75947-2
KCTD2NR_110835.2 linkn.365+3862T>G intron_variant Intron 3 of 7

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ATP5PDENST00000301587.9 linkc.344A>C p.Tyr115Ser missense_variant Exon 5 of 6 1 NM_006356.3 ENSP00000301587.4 O75947-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Mar 07, 2025
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.344A>C (p.Y115S) alteration is located in exon 5 (coding exon 4) of the ATP5H gene. This alteration results from a A to C substitution at nucleotide position 344, causing the tyrosine (Y) at amino acid position 115 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.42
BayesDel_addAF
Pathogenic
0.34
D
BayesDel_noAF
Pathogenic
0.24
CADD
Uncertain
23
DANN
Benign
0.95
DEOGEN2
Benign
0.33
T;.
Eigen
Uncertain
0.63
Eigen_PC
Uncertain
0.57
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Benign
0.71
T;T
M_CAP
Benign
0.040
D
MetaRNN
Pathogenic
0.87
D;D
MetaSVM
Uncertain
-0.019
T
MutationAssessor
Uncertain
2.9
M;.
PrimateAI
Uncertain
0.62
T
PROVEAN
Pathogenic
-5.5
D;D
REVEL
Uncertain
0.42
Sift
Uncertain
0.010
D;D
Sift4G
Uncertain
0.027
D;T
Polyphen
0.99
D;P
Vest4
0.67
MutPred
0.71
Gain of disorder (P = 0.0049);.;
MVP
0.54
MPC
0.51
ClinPred
0.99
D
GERP RS
4.5
RBP_binding_hub_radar
0.92
RBP_regulation_power_radar
2.6
Varity_R
0.51
gMVP
0.89

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-73035314; API