rs540554423

Variant names:

• chr19-1397469-C-G
• rs540554423
• NM_000156.6:c.601G>C

Your query was ambiguous. Multiple possible variants found:

• chr19-1397469-C-G
• chr19-1397469-C-T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_000156.6(GAMT):​c.601G>C​(p.Gly201Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G201S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: GAMT NM_000156.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.72
• Publications: 1 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 18 uncertain in NM_000156.6
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.889

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GAMT	NM_000156.6	c.601G>C	p.Gly201Arg	missense_variant	Exon 6 of 6	ENST00000252288.8	NP_000147.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GAMT	ENST00000252288.8	c.601G>C	p.Gly201Arg	missense_variant	Exon 6 of 6	1	NM_000156.6	ENSP00000252288.1
GAMT	ENST00000640762.1	c.532G>C	p.Gly178Arg	missense_variant	Exon 6 of 6	5		ENSP00000492031.1
GAMT	ENST00000640164.1	n.434G>C		non_coding_transcript_exon_variant	Exon 4 of 4	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.55
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.24
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.84	D;.
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Pathogenic	0.29	D
MetaRNN	Pathogenic	0.89	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.4	M;.
PhyloP100		4.7
PROVEAN	Pathogenic	-4.6	D;.
REVEL	Pathogenic	0.78
Sift	Uncertain	0.0020	D;.
Sift4G	Uncertain	0.0030	D;.
Polyphen		1.0	D;.
Vest4		0.85
MutPred		0.50		Gain of solvent accessibility (P = 0.0306);.;
MVP		0.96
ClinPred		0.97	D
GERP RS		5.1
Varity_R		0.66
Mutation Taster		=41/59	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

Other links and lift over

dbSNP: rs540554423; hg19: chr19-1397468;