2-175178399-G-C

Position:

• chr2-175178399-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Moderate PP5_Moderate

The NM_001689.5(ATP5MC3):​c.318C>G​(p.Asn106Lys) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ATP5MC3 NM_001689.5 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 2.36

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.896
• PP5: Variant 2-175178399-G-C is Pathogenic according to our data. Variant chr2-175178399-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 976731.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATP5MC3	NM_001689.5	c.318C>G	p.Asn106Lys	missense_variant	5/5	ENST00000284727.9	NP_001680.1
ATP5MC3	NM_001002258.5	c.318C>G	p.Asn106Lys	missense_variant	4/4		NP_001002258.1
ATP5MC3	NM_001190329.2	c.*654C>G		3_prime_UTR_variant	4/4		NP_001177258.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATP5MC3	ENST00000284727.9	c.318C>G	p.Asn106Lys	missense_variant	5/5	1	NM_001689.5	ENSP00000284727	P1
ATP5MC3	ENST00000392541.3	c.318C>G	p.Asn106Lys	missense_variant	4/4	1		ENSP00000376324	P1
ATP5MC3	ENST00000409194.5	c.318C>G	p.Asn106Lys	missense_variant	5/5	2		ENSP00000387317	P1
ATP5MC3	ENST00000497075.5	n.1100C>G		non_coding_transcript_exon_variant	4/4	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

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

Pathogenic, no assertion criteria provided

literature only

OMIM

May 04, 2023

- -

ATP5G3-associated disorder Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München

Nov 28, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Benign	-0.018	T
BayesDel_noAF	Benign	-0.26
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.45	T;T;T
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.95	.;.;D
M_CAP	Benign	0.079	D
MetaRNN	Pathogenic	0.90	D;D;D
MetaSVM	Benign	-0.38	T
MutationAssessor	Pathogenic	3.4	M;M;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-5.5	D;D;D
REVEL	Uncertain	0.44
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.93
MutPred		0.71		Gain of methylation at N106 (P = 0.0119);Gain of methylation at N106 (P = 0.0119);Gain of methylation at N106 (P = 0.0119);
MVP		0.76
MPC		1.3
ClinPred		0.99	D
GERP RS		3.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.90
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.36		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.36		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs757411192; hg19: chr2-176043127;