NM_006886.4:c.35A>G

Variant names:

• chr20-59030427-T-C
• rs387906929
• NM_006886.4:c.35A>G

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_006886.4(ATP5F1E):​c.35A>G​(p.Tyr12Cys) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ATP5F1E NM_006886.4 missense, splice_region
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 5.73
• Publications: 10 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: Likely_pathogenic. The variant received 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.954
• PP5: Variant 20-59030427-T-C is Pathogenic according to our data. Variant chr20-59030427-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 30551.Status of the report is no_assertion_criteria_provided, 0 stars.

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.35A>G	p.Tyr12Cys	missense splice_region	Exon 2 of 3	NP_008817.1	P56381
	SLMO2-ATP5E	NR_037929.1		n.739A>G		splice_region non_coding_transcript_exon	Exon 7 of 8
	SLMO2-ATP5E	NR_037930.1		n.480A>G		splice_region non_coding_transcript_exon	Exon 5 of 6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP5F1E	ENST00000243997.8	TSL:1 MANE Select	c.35A>G	p.Tyr12Cys	missense splice_region	Exon 2 of 3	ENSP00000243997.3	P56381
	ATP5F1E	ENST00000395659.1	TSL:1	c.35A>G	p.Tyr12Cys	missense splice_region	Exon 2 of 2	ENSP00000379019.1	P56381
	ATP5F1E	ENST00000395663.1	TSL:2	c.35A>G	p.Tyr12Cys	missense splice_region	Exon 2 of 3	ENSP00000379023.1	P56381

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Mitochondrial complex V (ATP synthase) deficiency, nuclear type 3 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.87	D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.40	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Uncertain	0.75	D
PhyloP100		5.7
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-9.0	D
REVEL	Pathogenic	0.90
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.97
MutPred		0.78		Loss of helix (P = 0.0041)
MVP		0.97
MPC		0.43
ClinPred		1.0	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.95
gMVP		0.67
Mutation Taster		=62/38	disease causing (ClinVar)

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: rs387906929; hg19: chr20-57605482;