2-175179201-T-C

Position:

• chr2-175179201-T-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Moderate BP6_Moderate

The NM_001689.5(ATP5MC3):​c.170A>G​(p.Gln57Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,882 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ATP5MC3 NM_001689.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.51

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_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08384699).
• BP6: Variant 2-175179201-T-C is Benign according to our data. Variant chr2-175179201-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 3131709.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.170A>G	p.Gln57Arg	missense_variant	4/5	ENST00000284727.9	NP_001680.1
ATP5MC3	NM_001002258.5	c.170A>G	p.Gln57Arg	missense_variant	3/4		NP_001002258.1
ATP5MC3	NM_001190329.2	c.170A>G	p.Gln57Arg	missense_variant	4/4		NP_001177258.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATP5MC3	ENST00000284727.9	c.170A>G	p.Gln57Arg	missense_variant	4/5	1	NM_001689.5	ENSP00000284727.4
ATP5MC3	ENST00000392541.3	c.170A>G	p.Gln57Arg	missense_variant	3/4	1		ENSP00000376324.3
ATP5MC3	ENST00000409194.5	c.170A>G	p.Gln57Arg	missense_variant	4/5	2		ENSP00000387317.1
ATP5MC3	ENST00000497075.5	n.298A>G		non_coding_transcript_exon_variant	4/4	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461882 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 727240

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: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000712 Hom.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 13, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	12
DANN	Benign	0.72
DEOGEN2	Benign	0.013	T;T;T
Eigen	Benign	-0.97
Eigen_PC	Benign	-0.78
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.18	.;.;T
M_CAP	Benign	0.0022	T
MetaRNN	Benign	0.084	T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-0.55	N;N;N
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.33	N;N;N
REVEL	Benign	0.039
Sift	Benign	0.75	T;T;T
Sift4G	Benign	0.83	T;T;T
Polyphen		0.0	B;B;B
Vest4		0.035
MutPred		0.31		Loss of helix (P = 0.0093);Loss of helix (P = 0.0093);Loss of helix (P = 0.0093);
MVP		0.22
MPC		0.45
ClinPred		0.033	T
GERP RS		-3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.022
gMVP		0.42

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

LitVar

Other links and lift over

dbSNP: rs1353360759; hg19: chr2-176043929;