7-141652792-A-AGG

Variant names:

• chr7-141652792-A-AGG
• rs1554405928
• NM_018238.4:c.1141_1142dupGG

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_018238.4(AGK):​c.1141_1142dupGG​(p.Ser382AlafsTer17) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: AGK NM_018238.4 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 2.36
• Publications: 0 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)

ENSG00000244701 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 14 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 6 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 7-141652792-A-AGG is Pathogenic according to our data. Variant chr7-141652792-A-AGG is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 524160.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018238.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGK	NM_018238.4	MANE Select	c.1141_1142dupGG	p.Ser382AlafsTer17	frameshift	Exon 16 of 16	NP_060708.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGK	ENST00000649286.2	MANE Select	c.1141_1142dupGG	p.Ser382AlafsTer17	frameshift	Exon 16 of 16	ENSP00000497280.1
	AGK	ENST00000648068.1		c.1141_1142dupGG	p.Ser382AlafsTer17	frameshift	Exon 16 of 16	ENSP00000498112.1
	AGK	ENST00000650547.1		c.1141_1142dupGG	p.Ser382AlafsTer17	frameshift	Exon 16 of 16	ENSP00000496789.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

May 02, 2018

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1141_1142dupGG variant in the AGK gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The c.1141_1142dupGG variant causes a frameshift starting with codon Serine 382, changes this amino acid to a Alanine residue, and creates a premature Stop codon at position 17 of the new reading frame, denoted p.Ser382AlafsX17. This variant is predicted to cause loss of normal protein function through protein truncation. The c.1141_1142dupGG variant is not observed in large population cohorts (Lek et al., 2016). We interpret c.1141_1142dupGG as a likely pathogenic variant.

Sengers syndrome;C3553494:Cataract 38 Pathogenic:1

Oct 28, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ser382Alafs*17) in the AGK gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 41 amino acid(s) of the AGK protein. This premature translational stop signal has been observed in individual(s) with clinical features of Sengers syndrome (Invitae). ClinVar contains an entry for this variant (Variation ID: 524160). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts a region of the AGK protein in which other variant(s) (p.Tyr390Serfs*9) have been determined to be pathogenic (Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.4

Splicing

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

Other links and lift over

dbSNP: rs1554405928; hg19: chr7-141352592;