rs540554423

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3_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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 33)

Consequence

GAMT
NM_000156.6 missense

Scores

11
6
1

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.72
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM1
In a domain RMT2 (size 223) in uniprot entity GAMT_HUMAN there are 36 pathogenic changes around while only 7 benign (84%) 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/exons MANE Protein UniProt
GAMTNM_000156.6 linkuse as main transcriptc.601G>C p.Gly201Arg missense_variant 6/6 ENST00000252288.8 NP_000147.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
GAMTENST00000252288.8 linkuse as main transcriptc.601G>C p.Gly201Arg missense_variant 6/61 NM_000156.6 ENSP00000252288 P1Q14353-1
GAMTENST00000640762.1 linkuse as main transcriptc.532G>C p.Gly178Arg missense_variant 6/65 ENSP00000492031
GAMTENST00000640164.1 linkuse as main transcriptn.434G>C non_coding_transcript_exon_variant 4/42

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
33

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;.
MutationTaster
Benign
1.0
D
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

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs540554423; hg19: chr19-1397468; API