21-25724650-G-T

Variant names:

• chr21-25724650-G-T
• rs1803181
• NM_001003703.2:c.317C>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001003703.2(ATP5PF):​c.317C>A​(p.Pro106His) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ATP5PF NM_001003703.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.20
• Publications: 2 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.37510264).

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.317C>A	p.Pro106His	missense	Exon 4 of 4	NP_001003703.1	P18859-1
	ATP5PF	NM_001003701.2		c.341C>A	p.Pro114His	missense	Exon 4 of 4	NP_001003701.1	P18859-2
	ATP5PF	NM_001003696.2		c.317C>A	p.Pro106His	missense	Exon 4 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.317C>A	p.Pro106His	missense	Exon 4 of 4	ENSP00000284971.3	P18859-1
	ATP5PF	ENST00000400093.3	TSL:1	c.317C>A	p.Pro106His	missense	Exon 4 of 4	ENSP00000382965.3	P18859-1
	ATP5PF	ENST00000457143.6	TSL:2	c.341C>A	p.Pro114His	missense	Exon 4 of 4	ENSP00000389649.2	P18859-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Uncertain	0.082	D
BayesDel_noAF	Benign	-0.12
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.028	T
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.37	T
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.38	T
MetaSVM	Benign	-0.42	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		4.2
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.16
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.011	D
Polyphen		1.0	D
Vest4		0.51
MutPred		0.27		Loss of sheet (P = 0.0181)
MVP		0.51
MPC		0.70
ClinPred		0.91	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.12
gMVP		0.23
Mutation Taster		=79/21	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: rs1803181; hg19: chr21-27096961;