rs147804855

Variant names:

• chr15-45369496-G-A
• rs147804855
• NM_001482.3:c.314C>T

Your query was ambiguous. Multiple possible variants found:

• chr15-45369496-G-A
• chr15-45369496-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. BP4 PM2_Supporting PS3_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_001482.3:c.314C>T variant in GATM is a missense variant that is predicted to result in the substitution of proline by leucine and amino acid position 105 (p.Pro105Leu). To our knowledge, this variant has not been reported in an individual with AGAT deficiency in the published literature. It is absent in gnomAD v4.1.0. (PM2_Supporting). When overexpressed in HeLa cells, the variant resulted in 0.6% wild-type activity (PMID:27233232; ClinVar Variation ID: 225913 - see Germline Functional Evidence section) which is below the threshold of the CCDS VCEP of <15% wild-type activity, indicating the the variant may impact the function of the protein (PS3_Supporting). The computational predictor REVEL gives a score of 0.066 which is below the threshold of 0.29, evidence that does not predict a damaging effect on AGAT function (BP4). There is a ClinVar entry for this variant (Variation ID: 225913). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for AGAT deficiency. GATM-specific ACMG/AMP criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 2.0.0): PS3_Supporting, PM2_Supporting, BP4.(Classification approved by the ClinGen CCDS VCEP on April 11, 2025). LINK:https://erepo.genome.network/evrepo/ui/classification/CA270169359/MONDO:0012996/025

• Frequency: Genomes: not found (cov: 32)
• Consequence: GATM NM_001482.3 missense
• Clinical Significance: Uncertain significance reviewed by expert panel U:1
• Conservation: PhyloP100: 4.90
• Publications: 3 publications found

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]

GATM Gene-Disease associations (from GenCC):

• AGAT deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Orphanet, Ambry Genetics, G2P
• Fanconi renotubular syndrome 1

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• primary Fanconi syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• BP4: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GATM	NM_001482.3	c.314C>T	p.Pro105Leu	missense_variant	Exon 3 of 9	ENST00000396659.8	NP_001473.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GATM	ENST00000396659.8	c.314C>T	p.Pro105Leu	missense_variant	Exon 3 of 9	1	NM_001482.3	ENSP00000379895.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Arginine:glycine amidinotransferase deficiency Uncertain:1

Apr 11, 2025

ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel, ClinGen

Significance: Uncertain significance

Review Status: reviewed by expert panel

Collection Method: curation

The NM_001482.3:c.314C>T variant in GATM is a missense variant that is predicted to result in the substitution of proline by leucine and amino acid position 105 (p.Pro105Leu). To our knowledge, this variant has not been reported in an individual with AGAT deficiency in the published literature. It is absent in gnomAD v4.1.0. (PM2_Supporting). When overexpressed in HeLa cells, the variant resulted in 0.6% wild-type activity (PMID: 27233232; ClinVar Variation ID: 225913 - see Germline Functional Evidence section) which is below the threshold of the CCDS VCEP of <15% wild-type activity, indicating the the variant may impact the function of the protein (PS3_Supporting). The computational predictor REVEL gives a score of 0.066 which is below the threshold of 0.29, evidence that does not predict a damaging effect on AGAT function (BP4). There is a ClinVar entry for this variant (Variation ID: 225913). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for AGAT deficiency. GATM-specific ACMG/AMP criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 2.0.0): PS3_Supporting, PM2_Supporting, BP4. (Classification approved by the ClinGen CCDS VCEP on April 11, 2025). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.055	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.57	D;.;.
Eigen	Benign	0.15
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.94	D;D;D
M_CAP	Benign	0.0063	T
MetaRNN	Benign	0.25	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.1	M;M;.
PhyloP100		4.9
PrimateAI	Benign	0.43	T
PROVEAN	Uncertain	-2.4	N;N;N
REVEL	Benign	0.066
Sift	Benign	0.19	T;T;D
Sift4G	Benign	0.30	T;T;.
Polyphen		0.055	B;B;.
Vest4		0.32
MVP		0.24
MPC		0.72
ClinPred		0.72	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.13
gMVP		0.79

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs147804855; hg19: chr15-45661694; COSMIC: COSV67541076; COSMIC: COSV67541076;