Genetic Variant NM_001689.5:c.236G>A (chr2-175179135-C-T) – ACMG Classification: Likely_pathogenic (8 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2PM5PP3_Strong

The NM_001689.5(ATP5MC3):c.236G>A(p.Gly79Asp) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G79V) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 33)

Consequence

ATP5MC3
NM_001689.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.91

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: Likely_pathogenic. The variant received 8 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr2-175179135-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 2500984.Status of the report is no_assertion_criteria_provided, 0 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.975

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.236G>A	p.Gly79Asp	missense	Exon 4 of 5	NP_001680.1	P48201
ATP5MC3	NM_001002258.5		c.236G>A	p.Gly79Asp	missense	Exon 3 of 4	NP_001002258.1	P48201
ATP5MC3	NM_001190329.2		c.236G>A	p.Gly79Asp	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.236G>A	p.Gly79Asp	missense	Exon 4 of 5	ENSP00000284727.4	P48201
ATP5MC3	ENST00000392541.3	TSL:1	c.236G>A	p.Gly79Asp	missense	Exon 3 of 4	ENSP00000376324.3	P48201
ATP5MC3	ENST00000941362.1		c.242G>A	p.Gly81Asp	missense	Exon 4 of 5	ENSP00000611421.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.37

BayesDel_noAF

Pathogenic

0.29

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.46

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

1.0

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.95

M_CAP

Uncertain

0.13

MetaRNN

Pathogenic

0.97

MetaSVM

Uncertain

0.65

MutationAssessor

Pathogenic

4.2

PhyloP100

7.9

PrimateAI

Pathogenic

0.85

PROVEAN

Pathogenic

-6.6

REVEL

Pathogenic

0.74

Sift

Uncertain

0.0010

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.94

MutPred

0.91

Gain of relative solvent accessibility (P = 0.09)

MVP

0.81

MPC

1.4

ClinPred

1.0

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.9

Varity_R

0.98

gMVP

0.99

Mutation Taster

=15/85

disease causing

(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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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