15-45369364-C-T

Position:

• chr15-45369364-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1 PP4_Strong PM2_Supporting PM3_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_001482.3:c.446G>A (p.Trp149Ter) variant in GATM is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 3/9 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). Three siblings and a cousin with AGAT deficiency are all homozygous for the variant (PM3_Supporting). The proband in this family has total absence of the creatine/phosphocreatine peak on brain MRS, low urine GAA and creatine but normal blood levels; AGAT activity in lymphoblasts <0.3 nmol/hr/mg protein (normal 12.6–23.4)(PP4_Strong). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 7302). In summary, this variant meets the criteria to be classified as pathogenic for AGAT deficiency. GATM-specific ACMG/AMP codes met, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes VCEP (Specifications Version 1.1.0): PVS1, PP4_Strong, PM3_Supporting, PM2_Supporting.(Classification approved by the ClinGen CCDS VCEP on June 6, 2022). LINK:https://erepo.genome.network/evrepo/ui/classification/CA340668/MONDO:0012996/025

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: GATM NM_001482.3 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:3 O:1
• Conservation: PhyloP100: 7.48

Genes affected

GATM (HGNC:4175): (glycine amidinotransferase) This gene encodes a mitochondrial enzyme that belongs to the amidinotransferase family. This enzyme is involved in creatine biosynthesis, whereby it catalyzes the transfer of a guanido group from L-arginine to glycine, resulting in guanidinoacetic acid, the immediate precursor of creatine. Mutations in this gene cause arginine:glycine amidinotransferase deficiency, an inborn error of creatine synthesis characterized by cognitive disability, language impairment, and behavioral disorders. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM3: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GATM	NM_001482.3	c.446G>A	p.Trp149Ter	stop_gained	3/9	ENST00000396659.8	NP_001473.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GATM	ENST00000396659.8	c.446G>A	p.Trp149Ter	stop_gained	3/9	1	NM_001482.3	ENSP00000379895	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461838 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727216

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Arginine:glycine amidinotransferase deficiency Pathogenic:3 Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Likely pathogenic, no assertion criteria provided	provider interpretation	Solve-RD Consortium	Jun 01, 2022	Variant confirmed as disease-causing by referring clinical team -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 2002	- -
Pathogenic, reviewed by expert panel	curation	ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel, ClinGen	Jun 06, 2022	The NM_001482.3:c.446G>A (p.Trp149Ter) variant in GATM is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 3/9 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). Three siblings and a cousin with AGAT deficiency are all homozygous for the variant (PM3_Supporting). The proband in this family has total absence of the creatine/phosphocreatine peak on brain MRS, low urine GAA and creatine but normal blood levels; AGAT activity in lymphoblasts <0.3 nmol/hr/mg protein (normal 12.6–23.4)(PP4_Strong). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 7302). In summary, this variant meets the criteria to be classified as pathogenic for AGAT deficiency. GATM-specific ACMG/AMP codes met, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes VCEP (Specifications Version 1.1.0): PVS1, PP4_Strong, PM3_Supporting, PM2_Supporting. (Classification approved by the ClinGen CCDS VCEP on June 6, 2022). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.66
CADD	Pathogenic	37
DANN	Uncertain	1.0
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.95
FATHMM_MKL	Pathogenic	0.99	D
MutationTaster	Benign	1.0	A;A
Vest4		0.86
GERP RS		6.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs80338737; hg19: chr15-45661562;