rs370421531

chr19-1398964-C-Achr19-1398964-C-Gchr19-1398964-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PM5 PP3_Moderate

The NM_000156.6(GAMT):c.522G>T(p.Trp174Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000031 in 1,613,322 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 Uncertain significance (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W174R) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: GAMT NM_000156.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 5.81

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_000156.6
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-1398966-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1420866.Status of the report is reviewed_by_expert_panel, 3 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.87

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GAMT	NM_000156.6	c.522G>T	p.Trp174Cys	missense_variant	5/6	ENST00000252288.8
GAMT	NM_138924.3	c.522G>T	p.Trp174Cys	missense_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GAMT	ENST00000252288.8	c.522G>T	p.Trp174Cys	missense_variant	5/6	1	NM_000156.6	P1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152192 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461130 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 726870

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152192 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74346

Gnomad4 AFR AF: 0.0000483

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: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 05, 2024

The p.W174C variant (also known as c.522G>T), located in coding exon 5 of the GAMT gene, results from a G to T substitution at nucleotide position 522. The tryptophan at codon 174 is replaced by cysteine, an amino acid with highly dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jul 01, 2023

GAMT: PM2, PP3 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.33
Cadd	Pathogenic	32
Dann	Uncertain	0.99
DEOGEN2	Pathogenic	0.84	D;.;.
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D;D;D
M_CAP	Pathogenic	0.76	D
MetaRNN	Pathogenic	0.87	D;D;D
MetaSVM	Uncertain	0.58	D
MutationAssessor	Pathogenic	3.0	M;.;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-4.2	D;.;D
REVEL	Pathogenic	0.81
Sift	Uncertain	0.0050	D;.;D
Sift4G	Uncertain	0.046	D;.;D
Polyphen		1.0	D;.;.
Vest4		0.90
MutPred		0.61		Loss of ubiquitination at K179 (P = 0.0656);.;Loss of ubiquitination at K179 (P = 0.0656);
MVP		0.98
MPC		0.80
ClinPred		0.99	D
GERP RS		4.0
Varity_R		0.78
gMVP		0.94

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

Publications

LitVar

Other links and lift over

dbSNP: rs370421531; hg19: chr19-1398963; COSMIC: COSV52038774; COSMIC: COSV52038774;