10-7802294-T-C

Variant names:

• chr10-7802294-T-C
• rs767137801
• NM_001001973.3:c.662T>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001001973.3(ATP5F1C):​c.662T>C​(p.Ile221Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ATP5F1C NM_001001973.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.97

Genes affected

ATP5F1C (HGNC:833): (ATP synthase F1 subunit gamma) 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 consists of three main subunits (a, b, c). This gene encodes the gamma subunit of the catalytic core. Alternatively spliced transcript variants encoding different isoforms have been identified. This gene also has a pseudogene on chromosome 14. [provided by RefSeq, Jul 2008]

LOC105376392 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP5F1C	NM_001001973.3	c.662T>C	p.Ile221Thr	missense_variant	Exon 7 of 10	ENST00000356708.12	NP_001001973.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP5F1C	ENST00000356708.12	c.662T>C	p.Ile221Thr	missense_variant	Exon 7 of 10	1	NM_001001973.3	ENSP00000349142.7

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 14, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.662T>C (p.I221T) alteration is located in exon 7 (coding exon 7) of the ATP5C1 gene. This alteration results from a T to C substitution at nucleotide position 662, causing the isoleucine (I) at amino acid position 221 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.48
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Benign	-0.090
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.49	T;.
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.80	T;T
M_CAP	Benign	0.0099	T
MetaRNN	Uncertain	0.52	D;D
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	1.9	L;L
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-3.2	D;D
REVEL	Uncertain	0.44
Sift	Uncertain	0.0040	D;D
Sift4G	Benign	0.17	T;T
Polyphen		0.62	P;.
Vest4		0.64
MutPred		0.44		Loss of stability (P = 0.0013);Loss of stability (P = 0.0013);
MVP		0.51
MPC		0.67
ClinPred		0.91	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.2
Varity_R		0.28
gMVP		0.72

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: rs767137801; hg19: chr10-7844257;