NM_018238.4:c.841C>T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_018238.4(AGK):c.841C>T(p.Arg281*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000112 in 1,613,308 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

AGK
NM_018238.4 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 1.70

Publications

4 publications found

Variant links:

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)

AGK links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 16 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PP5

Variant 7-141641362-C-T is Pathogenic according to our data. Variant chr7-141641362-C-T is described in CliVar as Pathogenic. Clinvar id is 30829.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-141641362-C-T is described in CliVar as Pathogenic. Clinvar id is 30829.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-141641362-C-T is described in CliVar as Pathogenic. Clinvar id is 30829.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-141641362-C-T is described in CliVar as Pathogenic. Clinvar id is 30829.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-141641362-C-T is described in CliVar as Pathogenic. Clinvar id is 30829.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-141641362-C-T is described in CliVar as Pathogenic. Clinvar id is 30829.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-141641362-C-T is described in CliVar as Pathogenic. Clinvar id is 30829.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-141641362-C-T is described in CliVar as Pathogenic. Clinvar id is 30829.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-141641362-C-T is described in CliVar as Pathogenic. Clinvar id is 30829.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-141641362-C-T is described in CliVar as Pathogenic. Clinvar id is 30829.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-141641362-C-T is described in CliVar as Pathogenic. Clinvar id is 30829.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-141641362-C-T is described in CliVar as Pathogenic. Clinvar id is 30829.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-141641362-C-T is described in CliVar as Pathogenic. Clinvar id is 30829.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-141641362-C-T is described in CliVar as Pathogenic. Clinvar id is 30829.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-141641362-C-T is described in CliVar as Pathogenic. Clinvar id is 30829.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-141641362-C-T is described in CliVar as Pathogenic. Clinvar id is 30829.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-141641362-C-T is described in CliVar as Pathogenic. Clinvar id is 30829.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-141641362-C-T is described in CliVar as Pathogenic. Clinvar id is 30829.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-141641362-C-T is described in CliVar as Pathogenic. Clinvar id is 30829.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-141641362-C-T is described in CliVar as Pathogenic. Clinvar id is 30829.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-141641362-C-T is described in CliVar as Pathogenic. Clinvar id is 30829.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-141641362-C-T is described in CliVar as Pathogenic. Clinvar id is 30829.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-141641362-C-T is described in CliVar as Pathogenic. Clinvar id is 30829.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-141641362-C-T is described in CliVar as Pathogenic. Clinvar id is 30829.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-141641362-C-T is described in CliVar as Pathogenic. Clinvar id is 30829.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AGK	NM_018238.4 link	c.841C>T	p.Arg281*	stop_gained	Exon 12 of 16	ENST00000649286.2	NP_060708.1	Q53H12-1A4D1U5
AGK	NM_001364948.3 link	c.841C>T	p.Arg281*	stop_gained	Exon 12 of 15		NP_001351877.1
AGK	XM_011516397.4 link	c.841C>T	p.Arg281*	stop_gained	Exon 12 of 16		XP_011514699.1	Q53H12-1A4D1U5
AGK	XM_024446835.2 link	c.841C>T	p.Arg281*	stop_gained	Exon 12 of 16		XP_024302603.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AGK	ENST00000649286.2 link	c.841C>T	p.Arg281*	stop_gained	Exon 12 of 16		NM_018238.4	ENSP00000497280.1		Q53H12-1

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152074

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000799

AC:

AN:

250428

AF XY:

0.0000148

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000116

AC:

AN:

1461234

Hom.:

Cov.:

AF XY:

0.0000193

AC XY:

AN XY:

726918

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33426

American (AMR)

AF:

0.00

AC:

AN:

44578

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26084

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86140

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53402

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5756

European-Non Finnish (NFE)

AF:

0.0000126

AC:

AN:

1111784

Other (OTH)

AF:

0.0000166

AC:

AN:

60368

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152074

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74266

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41416

American (AMR)

AF:

0.00

AC:

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4804

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68014

Other (OTH)

AF:

0.00

AC:

AN:

2084

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Sengers syndrome

Pathogenic:1

Feb 10, 2012

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

not provided

Pathogenic:1

Mar 13, 2017

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The R281X pathogenic variant in the AGK gene has been reported previously in two unrelated individuals with Sengers syndrome who were each compound heterozygous for the R281X variant and another loss-of-function variant (Mayr et al., 2012; Haghighi et al., 2014). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The R281X variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret R281X as a pathogenic variant. -

Sengers syndrome;C3553494:Cataract 38

Pathogenic:1

Apr 10, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change creates a premature translational stop signal (p.Arg281*) in the AGK gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in AGK are known to be pathogenic (PMID: 22284826). This variant is present in population databases (rs387907025, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with Sengers syndrome (PMID: 22284826, 25208612). ClinVar contains an entry for this variant (Variation ID: 30829). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.62

BayesDel_noAF

Pathogenic

0.31

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Pathogenic

0.74

Eigen_PC

Uncertain

0.58

FATHMM_MKL

Benign

0.58

PhyloP100

1.7

Vest4

0.93

GERP RS

5.5

Mutation Taster

=2/198

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over