NM_004046.6:c.1562C>A

Variant names:

• chr18-46084522-G-T
• NM_004046.6:c.1562C>A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_004046.6(ATP5F1A):​c.1562C>A​(p.Ala521Asp) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 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: 3.59

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 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=0.057930827).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP5F1A	NM_004046.6	c.1562C>A	p.Ala521Asp	missense_variant	Exon 11 of 12	ENST00000398752.11	NP_004037.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP5F1A	ENST00000398752.11	c.1562C>A	p.Ala521Asp	missense_variant	Exon 11 of 12	1	NM_004046.6	ENSP00000381736.5

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

Inborn genetic diseases Uncertain:1

Sep 30, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1562C>A (p.A521D) alteration is located in exon 12 (coding exon 11) of the ATP5A1 gene. This alteration results from a C to A substitution at nucleotide position 1562, causing the alanine (A) at amino acid position 521 to be replaced by an aspartic acid (D). 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	Benign	0.078
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	15
DANN	Benign	0.15
DEOGEN2	Benign	0.10	T;.;T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.92
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.93	.;D;D;D
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.058	T;T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-0.82	N;.;N;.
PrimateAI	Benign	0.33	T
PROVEAN	Benign	1.5	N;.;N;.
REVEL	Benign	0.14
Sift	Benign	1.0	T;.;T;.
Sift4G	Benign	1.0	T;T;T;T
Polyphen		0.0	B;.;B;.
Vest4		0.25
MutPred		0.44		Gain of disorder (P = 0.1365);.;Gain of disorder (P = 0.1365);.;
MVP		0.27
MPC		0.097
ClinPred		0.071	T
GERP RS		3.6
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.0
Varity_R		0.044
gMVP		0.29

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: chr18-43664488;