20-59032241-T-G

Position:

• chr20-59032241-T-G

Variant summary

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

The ENST00000243997.8(ATP5F1E):​c.11A>C​(p.Tyr4Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000138 in 1,447,678 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. Y4Y) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ATP5F1E ENST00000243997.8 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 5.34

Genes affected

ATP5F1E (HGNC:838): (ATP synthase F1 subunit epsilon) 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 epsilon subunit of the catalytic core. Two pseudogenes of this gene are located on chromosomes 4 and 13. Read-through transcripts that include exons from this gene are expressed from the upstream gene SLMO2.[provided by RefSeq, Mar 2011]

SLMO2-ATP5E (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/exons	MANE	Protein	UniProt
ATP5F1E	NM_006886.4	c.11A>C	p.Tyr4Ser	missense_variant	1/3	ENST00000243997.8	NP_008817.1
SLMO2-ATP5E	NR_037930.1	n.478-1812A>C		intron_variant, non_coding_transcript_variant
SLMO2-ATP5E	NR_037929.1	n.737-1812A>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATP5F1E	ENST00000243997.8	c.11A>C	p.Tyr4Ser	missense_variant	1/3	1	NM_006886.4	ENSP00000243997	P1
ATP5F1E	ENST00000395659.1	c.11A>C	p.Tyr4Ser	missense_variant	1/2	1		ENSP00000379019	P1
ATP5F1E	ENST00000395663.1	c.11A>C	p.Tyr4Ser	missense_variant	1/3	2		ENSP00000379023	P1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1447678 Hom.: 0 Cov.: 31 AF XY: 0.00000139 AC XY: 1 AN XY: 718754

Gnomad4 AFR exome AF: 0.0000600

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

Bravo AF: 0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 18, 2022	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 214130). This variant has not been reported in the literature in individuals affected with ATP5E-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tyrosine, which is neutral and polar, with serine, which is neutral and polar, at codon 4 of the ATP5E protein (p.Tyr4Ser). -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 16, 2014	p.Tyr4Ser (TAC>TCC): c.11 A>C in exon 1 of the ATP5E gene (NM_006886.2). The Y4S variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The Y4S variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant likely does not alter the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in LAPDH-MITOP panel(s). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.52
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.54	D;D;D
Eigen	Benign	-0.041
Eigen_PC	Benign	0.10
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.81	.;.;T
M_CAP	Uncertain	0.098	D
MetaRNN	Uncertain	0.68	D;D;D
MetaSVM	Benign	-0.73	T
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-3.2	D;D;D
REVEL	Uncertain	0.46
Sift	Benign	0.033	D;D;D
Sift4G	Benign	0.42	T;T;T
Polyphen		0.059	B;B;B
Vest4		0.86
MutPred		0.56		Gain of disorder (P = 0.003);Gain of disorder (P = 0.003);Gain of disorder (P = 0.003);
MVP		0.79
MPC		0.41
ClinPred		0.94	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.48
gMVP		0.46

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: rs373113507; hg19: chr20-57607296;