19-1399841-G-C

Variant names:

• chr19-1399841-G-C
• rs144630886
• NM_000156.6:c.279C>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_000156.6(GAMT):​c.279C>G​(p.Asp93Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D93V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GAMT NM_000156.6 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: -1.20
• Publications: 0 publications found

Genes affected

GAMT (HGNC:4136): (guanidinoacetate N-methyltransferase) The protein encoded by this gene is a methyltransferase that converts guanidoacetate to creatine, using S-adenosylmethionine as the methyl donor. Defects in this gene have been implicated in neurologic syndromes and muscular hypotonia, probably due to creatine deficiency and accumulation of guanidinoacetate in the brain of affected individuals. Two transcript variants encoding different isoforms have been described for this gene. Pseudogenes of this gene are found on chromosomes 2 and 13. [provided by RefSeq, Feb 2012]

GAMT Gene-Disease associations (from GenCC):

• guanidinoacetate methyltransferase deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 12 uncertain in NM_000156.6
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12100986).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000156.6. 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
	GAMT	NM_000156.6	MANE Select	c.279C>G	p.Asp93Glu	missense	Exon 2 of 6	NP_000147.1
	GAMT	NM_138924.3		c.279C>G	p.Asp93Glu	missense	Exon 2 of 5	NP_620279.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GAMT	ENST00000252288.8	TSL:1 MANE Select	c.279C>G	p.Asp93Glu	missense	Exon 2 of 6	ENSP00000252288.1
	GAMT	ENST00000447102.8	TSL:2	c.279C>G	p.Asp93Glu	missense	Exon 2 of 5	ENSP00000403536.2
	GAMT	ENST00000640762.1	TSL:5	c.210C>G	p.Asp70Glu	missense	Exon 2 of 6	ENSP00000492031.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

Deficiency of guanidinoacetate methyltransferase Uncertain:1

Mar 28, 2025

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.089	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	0.011
DANN	Benign	0.93
DEOGEN2	Benign	0.34	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.094	N
LIST_S2	Benign	0.74	T
M_CAP	Uncertain	0.086	D
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-0.87	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		-1.2
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.25
Sift	Benign	0.48	T
Sift4G	Benign	0.40	T
Polyphen		0.0010	B
Vest4		0.28
MutPred		0.48		Gain of MoRF binding (P = 0.2313)
MVP		0.61
MPC		0.14
ClinPred		0.20	T
GERP RS		-7.1
PromoterAI		-0.071	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.14
gMVP		0.41
Mutation Taster		=53/47	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs144630886; hg19: chr19-1399840;