19-1244118-T-G

Variant names:

• chr19-1244118-T-G
• rs1555745989
• NM_001687.5:c.317T>G

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_001687.5(ATP5F1D):​c.317T>G​(p.Val106Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V106A) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ATP5F1D NM_001687.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 7.38
• Publications: 0 publications found

Genes affected

ATP5F1D (HGNC:837): (ATP synthase F1 subunit delta) 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 delta subunit of the catalytic core. Alternatively spliced transcript variants encoding the same isoform have been identified. [provided by RefSeq, Jul 2008]

ATP5F1D Gene-Disease associations (from GenCC):

• mitochondrial complex V (ATP synthase) deficiency, nuclear type 5

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P
• mitochondrial proton-transporting ATP synthase complex deficiency

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.925
• PP5: Variant 19-1244118-T-G is Pathogenic according to our data. Variant chr19-1244118-T-G is described in ClinVar as Pathogenic. ClinVar VariationId is 489386.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001687.5. 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
	ATP5F1D	NM_001687.5	MANE Select	c.317T>G	p.Val106Gly	missense	Exon 3 of 4	NP_001678.1	P30049
	ATP5F1D	NM_001001975.2		c.317T>G	p.Val106Gly	missense	Exon 3 of 5	NP_001001975.1	P30049

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP5F1D	ENST00000215375.7	TSL:1 MANE Select	c.317T>G	p.Val106Gly	missense	Exon 3 of 4	ENSP00000215375.1	P30049
	ATP5F1D	ENST00000395633.5	TSL:1	c.317T>G	p.Val106Gly	missense	Exon 3 of 5	ENSP00000378995.1	P30049
	ATP5F1D	ENST00000588538.5	TSL:1	n.815T>G		non_coding_transcript_exon	Exon 2 of 3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Mitochondrial complex V (ATP synthase) deficiency, nuclear type 5 (1)
1	-	-	Mitochondrial disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.61	D
Eigen	Pathogenic	0.78
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.91	D
M_CAP	Pathogenic	0.47	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Uncertain	0.43	D
MutationAssessor	Pathogenic	3.6	H
PhyloP100		7.4
PrimateAI	Uncertain	0.57	T
PROVEAN	Pathogenic	-6.7	D
REVEL	Pathogenic	0.76
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.75
MutPred		0.70		Loss of stability (P = 9e-04)
MVP		0.63
MPC		1.4
ClinPred		1.0	D
GERP RS		4.6
Varity_R		0.93
gMVP		0.93
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.36		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.36		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1555745989; hg19: chr19-1244117;