rs1555777047

Variant names:

• chr19-1399146-G-C
• rs1555777047
• NM_000156.6:c.441C>G

Your query was ambiguous. Multiple possible variants found:

• chr19-1399146-G-C
• chr19-1399146-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PM5

The NM_000156.6(GAMT):​c.441C>G​(p.His147Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H147Y) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GAMT NM_000156.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.04

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 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
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GAMT	NM_000156.6	c.441C>G	p.His147Gln	missense_variant	Exon 4 of 6	ENST00000252288.8	NP_000147.1
GAMT	NM_138924.3	c.441C>G	p.His147Gln	missense_variant	Exon 4 of 5		NP_620279.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GAMT	ENST00000252288.8	c.441C>G	p.His147Gln	missense_variant	Exon 4 of 6	1	NM_000156.6	ENSP00000252288.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.75	D;.;.
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.87	D;D;D
M_CAP	Pathogenic	0.41	D
MetaRNN	Uncertain	0.72	D;D;D
MetaSVM	Uncertain	0.32	D
MutationAssessor	Uncertain	2.7	M;.;M
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-4.2	D;.;D
REVEL	Pathogenic	0.72
Sift	Uncertain	0.010	D;.;T
Sift4G	Benign	0.29	T;.;T
Polyphen		1.0	D;.;.
Vest4		0.77
MutPred		0.36		Loss of disorder (P = 0.1422);.;Loss of disorder (P = 0.1422);
MVP		0.95
MPC		0.63
ClinPred		0.98	D
GERP RS		3.4
Varity_R		0.84
gMVP		0.69

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: rs1555777047; hg19: chr19-1399145;