NM_018238.4:c.517C>T

Variant names:

• chr7-141615564-C-T
• rs387907024
• NM_018238.4:c.517C>T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP3 PP5

The NM_018238.4(AGK):​c.517C>T​(p.Gln173*) variant causes a stop gained, 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 pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: AGK NM_018238.4 stop_gained, splice_region
• Scores: Splicing: ADA: 0.9972
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 1.21
• Publications: 3 publications found

Genes affected

AGK (HGNC:21869): (acylglycerol kinase) The protein encoded by this gene is a mitochondrial membrane protein involved in lipid and glycerolipid metabolism. The encoded protein is a lipid kinase that catalyzes the formation of phosphatidic and lysophosphatidic acids. Defects in this gene have been associated with mitochondrial DNA depletion syndrome 10. [provided by RefSeq, Feb 2012]

AGK Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Sengers syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet
• total early-onset cataract

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• cataract 38

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

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.
• PP5: Variant 7-141615564-C-T is Pathogenic according to our data. Variant chr7-141615564-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 30827.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AGK	NM_018238.4	c.517C>T	p.Gln173*	stop_gained, splice_region_variant	Exon 8 of 16	ENST00000649286.2	NP_060708.1
AGK	NM_001364948.3	c.517C>T	p.Gln173*	stop_gained, splice_region_variant	Exon 8 of 15		NP_001351877.1
AGK	XM_011516397.4	c.517C>T	p.Gln173*	stop_gained, splice_region_variant	Exon 8 of 16		XP_011514699.1
AGK	XM_024446835.2	c.517C>T	p.Gln173*	stop_gained, splice_region_variant	Exon 8 of 16		XP_024302603.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AGK	ENST00000649286.2	c.517C>T	p.Gln173*	stop_gained, splice_region_variant	Exon 8 of 16		NM_018238.4	ENSP00000497280.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Sengers syndrome Pathogenic:1

Feb 10, 2012

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.63
CADD	Pathogenic	42
DANN	Uncertain	1.0
Eigen	Pathogenic	0.79
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Uncertain	0.86	D
PhyloP100		1.2
Vest4		0.88
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=1/199	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.86
SpliceAI score (max)		0.21		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.21		Position offset: 1

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

Other links and lift over

dbSNP: rs387907024; hg19: chr7-141315364;