2-175179135-C-A

Position:

• chr2-175179135-C-A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The ENST00000284727.9(ATP5MC3):​c.236G>T​(p.Gly79Val) 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. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ATP5MC3 ENST00000284727.9 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.91

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 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.968
• PP5: Variant 2-175179135-C-A is Pathogenic according to our data. Variant chr2-175179135-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 2500984.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATP5MC3	NM_001689.5	c.236G>T	p.Gly79Val	missense_variant	4/5	ENST00000284727.9	NP_001680.1
ATP5MC3	NM_001002258.5	c.236G>T	p.Gly79Val	missense_variant	3/4		NP_001002258.1
ATP5MC3	NM_001190329.2	c.236G>T	p.Gly79Val	missense_variant	4/4		NP_001177258.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATP5MC3	ENST00000284727.9	c.236G>T	p.Gly79Val	missense_variant	4/5	1	NM_001689.5	ENSP00000284727.4
ATP5MC3	ENST00000392541.3	c.236G>T	p.Gly79Val	missense_variant	3/4	1		ENSP00000376324.3
ATP5MC3	ENST00000409194.5	c.236G>T	p.Gly79Val	missense_variant	4/5	2		ENSP00000387317.1
ATP5MC3	ENST00000497075.5	n.364G>T		non_coding_transcript_exon_variant	4/4	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Dystonia, early-onset, and/or spastic paraplegia Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 04, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Pathogenic	30
DANN	Uncertain	0.99
DEOGEN2	Benign	0.36	T;T;T
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.97	.;.;D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.97	D;D;D
MetaSVM	Uncertain	0.23	D
MutationAssessor	Pathogenic	4.2	H;H;H
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-8.3	D;D;D
REVEL	Uncertain	0.63
Sift	Uncertain	0.016	D;D;D
Sift4G	Uncertain	0.018	D;D;D
Polyphen		0.91	P;P;P
Vest4		0.96
MutPred		0.88		Gain of helix (P = 0.0696);Gain of helix (P = 0.0696);Gain of helix (P = 0.0696);
MVP		0.83
MPC		1.4
ClinPred		1.0	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9
Varity_R		0.91
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-176043863; COSMIC: COSV52976623; COSMIC: COSV52976623;