Genetic Variant NM_001689.5:c.128C>A (chr2-175179243-G-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_001689.5(ATP5MC3):c.128C>A(p.Thr43Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T43M) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Consequence

ATP5MC3
NM_001689.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.23

Publications

0 publications found

Variant links:

Genes affected

ATP5MC3 (HGNC:843): (ATP synthase membrane subunit c locus 3) 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 seems to have nine subunits (a, b, c, d, e, f, g, F6 and 8). This gene is one of three genes that encode subunit c of the proton channel. Each of the three genes have distinct mitochondrial import sequences but encode the identical mature protein. Alternatively spliced transcript variants encoding different proteins have been identified. [provided by RefSeq, Jun 2010]

ATP5MC3 Gene-Disease associations (from GenCC):

dystonia, early-onset, and/or spastic paraplegia
Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics

ATP5MC3 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=0.10826504).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001689.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ATP5MC3	NM_001689.5	MANE Select	c.128C>A	p.Thr43Lys	missense	Exon 4 of 5	NP_001680.1	P48201
ATP5MC3	NM_001002258.5		c.128C>A	p.Thr43Lys	missense	Exon 3 of 4	NP_001002258.1	P48201
ATP5MC3	NM_001190329.2		c.128C>A	p.Thr43Lys	missense	Exon 4 of 4	NP_001177258.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ATP5MC3	ENST00000284727.9	TSL:1 MANE Select	c.128C>A	p.Thr43Lys	missense	Exon 4 of 5	ENSP00000284727.4	P48201
ATP5MC3	ENST00000392541.3	TSL:1	c.128C>A	p.Thr43Lys	missense	Exon 3 of 4	ENSP00000376324.3	P48201
ATP5MC3	ENST00000941362.1		c.134C>A	p.Thr45Lys	missense	Exon 4 of 5	ENSP00000611421.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000400

AC:

AN:

250272

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.44

CADD

Benign

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.029

Eigen

Benign

-0.31

Eigen_PC

Benign

-0.24

FATHMM_MKL

Benign

0.66

LIST_S2

Benign

0.42

M_CAP

Benign

0.0092

MetaRNN

Benign

0.11

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.95

PhyloP100

2.2

PrimateAI

Benign

0.35

PROVEAN

Benign

-1.1

REVEL

Benign

0.047

Sift

Benign

0.056

Sift4G

Benign

0.37

Polyphen

0.18

Vest4

0.29

MutPred

0.32

Gain of ubiquitination at T43 (P = 0.0109)

MVP

0.35

MPC

0.54

ClinPred

0.14

GERP RS

4.9

Varity_R

0.049

gMVP

0.69

Mutation Taster

=90/10

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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