chr2-175181359-G-A

Variant names:

• chr2-175181359-G-A
• rs370456305
• NM_001689.5:c.35C>T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001689.5(ATP5MC3):​c.35C>T​(p.Ser12Phe) 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 benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 34)
• Consequence: ATP5MC3 NM_001689.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.95

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.33869466).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP5MC3	NM_001689.5	c.35C>T	p.Ser12Phe	missense_variant	Exon 2 of 5	ENST00000284727.9	NP_001680.1
ATP5MC3	NM_001002258.5	c.35C>T	p.Ser12Phe	missense_variant	Exon 1 of 4		NP_001002258.1
ATP5MC3	NM_001190329.2	c.35C>T	p.Ser12Phe	missense_variant	Exon 2 of 4		NP_001177258.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP5MC3	ENST00000284727.9	c.35C>T	p.Ser12Phe	missense_variant	Exon 2 of 5	1	NM_001689.5	ENSP00000284727.4

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD3 exomes AF: 0.00000402 AC: 1 AN: 248974 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 134900

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000889

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.093	T
BayesDel_noAF	Benign	-0.37
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Benign	0.059	T;T;T
Eigen	Benign	0.16
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.52	.;.;T
M_CAP	Benign	0.0084	T
MetaRNN	Benign	0.34	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.93	L;L;L
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-2.6	D;D;D
REVEL	Benign	0.099
Sift	Benign	0.15	T;T;T
Sift4G	Benign	0.29	T;T;T
Polyphen		0.042	B;B;B
Vest4		0.33
MutPred		0.48		Loss of helix (P = 0.028);Loss of helix (P = 0.028);Loss of helix (P = 0.028);
MVP		0.28
MPC		0.44
ClinPred		0.93	D
GERP RS		5.1
Varity_R		0.50
gMVP		0.59

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs370456305; hg19: chr2-176046087;