20-59032224-G-T

Variant names:

• chr20-59032224-G-T
• rs770225638
• NM_006886.4:c.28C>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_006886.4(ATP5F1E):​c.28C>A​(p.Leu10Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000417 in 1,438,152 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L10F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000042 (0 hom.)
• Consequence: ATP5F1E NM_006886.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.23
• Publications: 0 publications found

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]

ATP5F1E Gene-Disease associations (from GenCC):

• mitochondrial proton-transporting ATP synthase complex deficiency

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• mitochondrial complex V (ATP synthase) deficiency, nuclear type 3

  Inheritance: AR, Unknown Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

SLMO2-ATP5E (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006886.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP5F1E	NM_006886.4	MANE Select	c.28C>A	p.Leu10Ile	missense	Exon 1 of 3	NP_008817.1	P56381
	SLMO2-ATP5E	NR_037929.1		n.737-1795C>A		intron	N/A
	SLMO2-ATP5E	NR_037930.1		n.478-1795C>A		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP5F1E	ENST00000243997.8	TSL:1 MANE Select	c.28C>A	p.Leu10Ile	missense	Exon 1 of 3	ENSP00000243997.3	P56381
	ATP5F1E	ENST00000395659.1	TSL:1	c.28C>A	p.Leu10Ile	missense	Exon 1 of 2	ENSP00000379019.1	P56381
	ATP5F1E	ENST00000395663.1	TSL:2	c.28C>A	p.Leu10Ile	missense	Exon 1 of 3	ENSP00000379023.1	P56381

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000417 AC: 6 AN: 1438152 Hom.: 0 Cov.: 31 AF XY: 0.00000421 AC XY: 3 AN XY: 713090

African (AFR) AF: 0.00 AC: 0 AN: 33206

American (AMR) AF: 0.00 AC: 0 AN: 41006

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25538

East Asian (EAS) AF: 0.000155 AC: 6 AN: 38826

South Asian (SAS) AF: 0.00 AC: 0 AN: 82706

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50192

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5476

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1101710

Other (OTH) AF: 0.00 AC: 0 AN: 59492

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Uncertain	0.074	D
BayesDel_noAF	Benign	-0.13
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.29	T
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.82	T
M_CAP	Uncertain	0.21	D
MetaRNN	Uncertain	0.48	T
MetaSVM	Uncertain	0.16	D
PhyloP100		2.2
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-1.3	N
REVEL	Uncertain	0.47
Sift	Benign	0.096	T
Sift4G	Benign	0.18	T
Polyphen		0.94	P
Vest4		0.28
MutPred		0.60		Loss of helix (P = 0.0795)
MVP		0.75
MPC		0.11
ClinPred		1.0	D
GERP RS		4.9
PromoterAI		0.034	Neutral
Varity_R		0.39
gMVP		0.11
Mutation Taster		=77/23	polymorphism

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

Other links and lift over

dbSNP: rs770225638; hg19: chr20-57607279;