chr18-46084287-C-T

Position:

• chr18-46084287-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_004046.6(ATP5F1A):​c.1657G>A​(p.Ala553Thr) 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 benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ATP5F1A NM_004046.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.20

Genes affected

ATP5F1A (HGNC:823): (ATP synthase F1 subunit alpha) This gene encodes a subunit of mitochondrial ATP synthase. Mitochondrial ATP synthase catalyzes ATP synthesis, using 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 alpha subunit of the catalytic core. Alternatively spliced transcript variants encoding the different isoforms have been identified. Pseudogenes of this gene are located on chromosomes 9, 2, and 16. [provided by RefSeq, Mar 2012]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), ATP5F1A. . Gene score misZ 2.437 (greater than the threshold 3.09). Trascript score misZ 3.1515 (greater than threshold 3.09). GenCC has associacion of gene with mitochondrial complex V (ATP synthase) deficiency nuclear type 4B, mitochondrial proton-transporting ATP synthase complex deficiency, combined oxidative phosphorylation deficiency 22, mitochondrial complex V (ATP synthase) deficiency, nuclear type 4A, mitochondrial disease.
• BP4: Computational evidence support a benign effect (MetaRNN=0.19091141).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATP5F1A	NM_004046.6	c.1657G>A	p.Ala553Thr	missense_variant	12/12	ENST00000398752.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP5F1A	ENST00000398752.11	c.1657G>A	p.Ala553Thr	missense_variant	12/12	1	NM_004046.6	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

May 01, 2023

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Uncertain	0.018	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.17	T;.;T;.
Eigen	Benign	-0.0080
Eigen_PC	Benign	0.027
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.91	.;D;D;D
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.19	T;T;T;T
MetaSVM	Benign	-0.73	T
MutationAssessor	Uncertain	2.8	M;.;M;.
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.75	N;.;N;.
REVEL	Benign	0.26
Sift	Uncertain	0.0010	D;.;D;.
Sift4G	Pathogenic	0.0010	D;D;D;D
Polyphen		0.69	P;.;P;.
Vest4		0.27
MutPred		0.37		Gain of disorder (P = 0.1674);.;Gain of disorder (P = 0.1674);.;
MVP		0.74
MPC		0.12
ClinPred		0.72	D
GERP RS		1.9
Varity_R		0.080
gMVP		0.51

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: chr18-43664253;