18-46084362-C-T

Variant names:

• chr18-46084362-C-T
• NM_004046.6:c.1582G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_004046.6(ATP5F1A):​c.1582G>A​(p.Ala528Thr) variant causes a missense, splice region 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. 19/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ATP5F1A NM_004046.6 missense, splice_region
• Scores: Splicing: ADA: 0.00009280
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.438
• Publications: 0 publications found

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]

ATP5F1A Gene-Disease associations (from GenCC):

• mitochondrial complex V (ATP synthase) deficiency, nuclear type 4A

  Inheritance: AD Classification: STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• mitochondrial complex V (ATP synthase) deficiency, nuclear type 4B

  Inheritance: AR Classification: STRONG Submitted by: G2P
• mitochondrial disease

  Inheritance: AR Classification: MODERATE Submitted by: Illumina
• mitochondrial proton-transporting ATP synthase complex deficiency

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• combined oxidative phosphorylation deficiency 22

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

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.049441397).
• BP6: Variant 18-46084362-C-T is Benign according to our data. Variant chr18-46084362-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 3457708.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004046.6. 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
	ATP5F1A	NM_004046.6	MANE Select	c.1582G>A	p.Ala528Thr	missense splice_region	Exon 12 of 12	NP_004037.1	P25705-1
	ATP5F1A	NM_001001937.2		c.1582G>A	p.Ala528Thr	missense splice_region	Exon 13 of 13	NP_001001937.1	P25705-1
	ATP5F1A	NM_001257334.2		c.1516G>A	p.Ala506Thr	missense splice_region	Exon 12 of 12	NP_001244263.1	P25705-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP5F1A	ENST00000398752.11	TSL:1 MANE Select	c.1582G>A	p.Ala528Thr	missense splice_region	Exon 12 of 12	ENSP00000381736.5	P25705-1
	ATP5F1A	ENST00000282050.6	TSL:5	c.1582G>A	p.Ala528Thr	missense splice_region	Exon 13 of 13	ENSP00000282050.2	P25705-1
	ATP5F1A	ENST00000858814.1		c.1564G>A	p.Ala522Thr	missense splice_region	Exon 12 of 12	ENSP00000528873.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	0.91
DANN	Benign	0.71
DEOGEN2	Benign	0.10	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.071	N
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.049	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	-1.0	N
PhyloP100		-0.44
PrimateAI	Benign	0.30	T
PROVEAN	Benign	0.24	N
REVEL	Benign	0.24
Sift	Benign	0.73	T
Sift4G	Benign	0.58	T
Polyphen		0.0	B
Vest4		0.099
MutPred		0.24		Loss of stability (P = 0.0827)
MVP		0.34
MPC		0.064
ClinPred		0.10	T
GERP RS		-6.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.019
gMVP		0.14

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000093
dbscSNV1_RF	Benign	0.020
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

hg19: chr18-43664328; COSMIC: COSV56359583; COSMIC: COSV56359583;