21-25729661-T-C

Variant names:

• chr21-25729661-T-C
• rs2034705101
• NM_001003703.2:c.134A>G

Variant summary

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

The NM_001003703.2(ATP5PF):​c.134A>G​(p.Asp45Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ATP5PF NM_001003703.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.79
• Publications: 0 publications found

Genes affected

ATP5PF (HGNC:847): (ATP synthase peripheral stalk subunit F6) Mitochondrial ATP synthase catalyzes ATP synthesis, utilizing an electrochemical gradient of protons across the inner membrane during oxidative phosphorylation. It is composed of two linked multi-subunit complexes: the soluble catalytic core, F1, and the membrane-spanning component, Fo, which comprises the proton channel. The F1 complex consists of 5 different subunits (alpha, beta, gamma, delta, and epsilon) assembled in a ratio of 3 alpha, 3 beta, and a single representative of the other 3. The Fo complex has nine subunits (a, b, c, d, e, f, g, F6 and 8). This gene encodes the F6 subunit of the Fo complex. The F6 subunit is required for F1 and Fo interactions. Alternatively spliced transcript variants encoding different isoforms have been identified for this gene. This gene has 1 or more pseudogenes. [provided by RefSeq, Feb 2016]

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_001003703.2. 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
	ATP5PF	NM_001003703.2	MANE Select	c.134A>G	p.Asp45Gly	missense	Exon 2 of 4	NP_001003703.1	P18859-1
	ATP5PF	NM_001003701.2		c.158A>G	p.Asp53Gly	missense	Exon 2 of 4	NP_001003701.1	P18859-2
	ATP5PF	NM_001003696.2		c.134A>G	p.Asp45Gly	missense	Exon 2 of 4	NP_001003696.1	P18859-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP5PF	ENST00000284971.8	TSL:1 MANE Select	c.134A>G	p.Asp45Gly	missense	Exon 2 of 4	ENSP00000284971.3	P18859-1
	ATP5PF	ENST00000400093.3	TSL:1	c.134A>G	p.Asp45Gly	missense	Exon 2 of 4	ENSP00000382965.3	P18859-1
	ATP5PF	ENST00000400099.5	TSL:5	c.134A>G	p.Asp45Gly	missense	Exon 2 of 5	ENSP00000382971.1	A8MUH2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.39
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.16
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.48	T
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.020	T
MetaRNN	Uncertain	0.74	D
MetaSVM	Uncertain	0.033	D
MutationAssessor	Pathogenic	3.3	M
PhyloP100		6.8
PrimateAI	Uncertain	0.61	T
PROVEAN	Pathogenic	-5.5	D
REVEL	Uncertain	0.40
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.013	D
Polyphen		0.99	D
Vest4		0.87
MutPred		0.42		Loss of stability (P = 0.0174)
MVP		0.55
MPC		0.27
ClinPred		0.99	D
GERP RS		5.0
Varity_R		0.78
gMVP		0.62
Mutation Taster		=33/67	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2034705101; hg19: chr21-27101972;