rs746709222

Positions:

chr7-141614164-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_018238.4(AGK):c.409C>T(p.Arg137Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.0000501 in 1,536,542 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: 33)

Exomes 𝑓: 0.000055 ( 0 hom. )

Consequence

AGK
NM_018238.4 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 3.68

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 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;

PP5

Variant 7-141614164-C-T is Pathogenic according to our data. Variant chr7-141614164-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 209130.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-141614164-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
AGK	NM_018238.4 linkuse as main transcript	c.409C>T	p.Arg137Ter	stop_gained	7/16	ENST00000649286.2	NP_060708.1
AGK	NM_001364948.3 linkuse as main transcript	c.409C>T	p.Arg137Ter	stop_gained	7/15		NP_001351877.1
AGK	XM_011516397.4 linkuse as main transcript	c.409C>T	p.Arg137Ter	stop_gained	7/16		XP_011514699.1
AGK	XM_024446835.2 linkuse as main transcript	c.409C>T	p.Arg137Ter	stop_gained	7/16		XP_024302603.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AGK	ENST00000649286.2 linkuse as main transcript	c.409C>T	p.Arg137Ter	stop_gained	7/16		NM_018238.4	ENSP00000497280	P1	Q53H12-1

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152068

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

GnomAD3 exomes

AF:

0.0000275

AC:

AN:

217828

Hom.:

AF XY:

0.0000253

AC XY:

AN XY:

118724

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000269

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000196

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000549

AC:

AN:

1384474

Hom.:

Cov.:

AF XY:

0.0000478

AC XY:

AN XY:

690460

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000165

Gnomad4 SAS exome

AF:

0.0000128

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000631

Gnomad4 OTH exome

AF:

0.0000349

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152068

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74274

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000658

Hom.:

Bravo

AF:

0.0000264

ExAC

AF:

0.0000577

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Sengers syndrome

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jul 15, 2013	This nonsense variant is categorized as deleterious according to ACMG guidelines (PMID:18414213). It was found once in our laboratory in trans with a deleterious intronic variant [c.424-3C>G] in an 18-year-old male with intellectual disability, hypotonia, muscle pain and weakness, congenital cataracts and glaucoma, ptosis, and dilated cardiomyopathy -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Jun 11, 2020	Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0106 - This gene is known to be associated with autosomal recessive disease. (N) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (exon 7 of 16). (P) 0251 - Variant is heterozygous. (N) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (7 heterozygotes, 0 homozygotes). (P) 0701 - Comparable variants have very strong previous evidence for pathogenicity. Other variants predicted to cause NMD have been reported as pathogenic in individuals with Sengers syndrome (ClinVar, PMID: 25208612) (P) 0801 - Strong previous evidence of pathogenicity in unrelated individuals. The variant has been previously reported in patients with Sengers syndrome (ClinVar, PMID: 25208612). (P) 1201 - Heterozygous variant detected in trans with a second (at least likely) pathogenic heterozygous variant in a recessive disease. (P) 1206 - Variant is paternally inherited. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign -
Pathogenic, no assertion criteria provided	curation	Department of Heart Center, Qingdao Women and Children's Hospital	-	- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Sep 18, 2017

The R137X pathogenic variant in the AGK gene has been reported previously in the homozygous state in two unrelated individuals with Sengers syndrome (Haghighi et al., 2014). In addition, the R137X variant is reported as pathogenic in ClinVar by a different clinical laboratory, but additional evidence is not available (ClinVar SCV00245448.1; Landrum et al., 2015). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The R137X 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 R137X as a pathogenic variant. -

Sengers syndrome;C3553494:Cataract 38

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 24, 2023

This sequence change creates a premature translational stop signal (p.Arg137*) 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 (rs746709222, gnomAD 0.03%). This premature translational stop signal has been observed in individuals with Sengers syndrome (PMID: 25208612). ClinVar contains an entry for this variant (Variation ID: 209130). For these reasons, this variant has been classified as Pathogenic. -

Trichohepatoenteric syndrome 1

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Sep 01, 2017

This nonsense variant is categorized as deleterious according to ACMG guidelines (PMID:18414213) and was found once in our laboratory homozygous in a 9-month-old male with motor delays, dysmorphisms, chronic secretory diarrhea, hypothyroidism, cholestatsis, anemia, alopecia. Heterozygotes are expected to be asymptomatic carriers. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.41

BayesDel_noAF

Pathogenic

0.60

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

0.75

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Uncertain

0.93

MutationTaster

Benign

1.0

A;A;A

Vest4

0.93

GERP RS

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over