17-75040142-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_006356.3(ATP5PD):​c.241G>A​(p.Val81Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,611,608 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)
Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

ATP5PD
NM_006356.3 missense

Scores

3
16

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.95
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.2661485).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ATP5PDNM_006356.3 linkc.241G>A p.Val81Met missense_variant Exon 4 of 6 ENST00000301587.9 NP_006347.1 O75947-1A0PJH2
ATP5PDNM_001003785.2 linkc.220-871G>A intron_variant Intron 3 of 4 NP_001003785.1 O75947-2
KCTD2NR_110835.2 linkn.365+4785C>T intron_variant Intron 3 of 7

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ATP5PDENST00000301587.9 linkc.241G>A p.Val81Met missense_variant Exon 4 of 6 1 NM_006356.3 ENSP00000301587.4 O75947-1

Frequencies

GnomAD3 genomes
AF:
0.00000659
AC:
1
AN:
151830
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000658
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251450
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135898
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 SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000879
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000206
AC:
3
AN:
1459778
Hom.:
0
Cov.:
30
AF XY:
0.00000138
AC XY:
1
AN XY:
726216
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.0000187
Gnomad4 NFE exome
AF:
0.00000180
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000659
AC:
1
AN:
151830
Hom.:
0
Cov.:
31
AF XY:
0.0000135
AC XY:
1
AN XY:
74158
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.0000658
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000756

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Feb 20, 2025
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.241G>A (p.V81M) alteration is located in exon 4 (coding exon 3) of the ATP5H gene. This alteration results from a G to A substitution at nucleotide position 241, causing the valine (V) at amino acid position 81 to be replaced by a methionine (M). 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
Benign
0.13
BayesDel_addAF
Benign
-0.12
T
BayesDel_noAF
Benign
-0.41
CADD
Benign
13
DANN
Uncertain
0.98
DEOGEN2
Benign
0.083
T
Eigen
Benign
-0.51
Eigen_PC
Benign
-0.46
FATHMM_MKL
Uncertain
0.89
D
LIST_S2
Benign
0.70
T
M_CAP
Benign
0.028
D
MetaRNN
Benign
0.27
T
MetaSVM
Benign
-0.91
T
MutationAssessor
Uncertain
2.7
M
PrimateAI
Benign
0.39
T
PROVEAN
Benign
-0.50
N
REVEL
Benign
0.078
Sift
Benign
0.11
T
Sift4G
Benign
0.092
T
Polyphen
0.020
B
Vest4
0.31
MutPred
0.49
Gain of ubiquitination at K78 (P = 0.0817);
MVP
0.23
MPC
0.22
ClinPred
0.10
T
GERP RS
-1.2
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.023
gMVP
0.44

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.040
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: rs760553279; hg19: chr17-73036237; API