GAMT p.Trp45Arg

Variant names:

• chr19-1401344-A-G
• NM_000156.6:c.133T>C
• GAMT p.Trp45Arg

Your query was ambiguous. Multiple possible variants found:

• chr19-1401344-A-G
• chr19-1401344-A-T
• chr19-1401342-CCA-ACG
• chr19-1401342-CCA-GCG
• chr19-1401342-CCA-TCG
• chr19-1401342-CCA-TCT

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PS1_Very_Strong PM1 PM2 PP3_Strong

The NM_000156.6(GAMT):​c.133T>C​(p.Trp45Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar. The gene GAMT is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: GAMT NM_000156.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.92
• 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: Labcorp Genetics (formerly Invitae), Orphanet, G2P, Ambry Genetics, ClinGen

ACMG classification

Specifications for GAMT are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

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

• PS1: Transcript NM_000156.6 (GAMT) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 24 uncertain in NM_000156.6
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.974

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GAMT	NM_000156.6	MANE Select	c.133T>C	p.Trp45Arg	missense	Exon 1 of 6	NP_000147.1	Q14353-1
	GAMT	NM_138924.3		c.133T>C	p.Trp45Arg	missense	Exon 1 of 5	NP_620279.1	Q14353-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GAMT	ENST00000252288.8	TSL:1 MANE Select	c.133T>C	p.Trp45Arg	missense	Exon 1 of 6	ENSP00000252288.1	Q14353-1
	GAMT	ENST00000902474.1		c.133T>C	p.Trp45Arg	missense	Exon 1 of 6	ENSP00000572533.1
	GAMT	ENST00000447102.8	TSL:2	c.133T>C	p.Trp45Arg	missense	Exon 1 of 5	ENSP00000403536.2	Q14353-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1386396 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 688466

African (AFR) AF: 0.00 AC: 0 AN: 29060

American (AMR) AF: 0.00 AC: 0 AN: 38536

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24468

East Asian (EAS) AF: 0.00 AC: 0 AN: 33298

South Asian (SAS) AF: 0.00 AC: 0 AN: 78998

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 36148

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4728

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1083616

Other (OTH) AF: 0.00 AC: 0 AN: 57544

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.49
CADD	Pathogenic	33
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.92	D
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.77	T
M_CAP	Pathogenic	0.72	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Pathogenic	3.8	H
PhyloP100		8.9
PrimateAI	Pathogenic	0.94	D
PROVEAN	Pathogenic	-12	D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
PromoterAI		0.047	Neutral
Varity_R		0.96
gMVP		0.91
Mutation Taster		=3/97	disease causing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr19-1401343;