Genetic Variant GAMT:p.His147Gln (chr19-1399146-G-C) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PM5

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 nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in 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

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.04

Publications

0 publications found

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]

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

GAMT links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr19-1399148-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 2446460.Status of the report is reviewed_by_expert_panel, 3 stars.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GAMT	NM_000156.6	MANE Select	c.441C>G	p.His147Gln	missense	Exon 4 of 6	NP_000147.1
	GAMT	NM_138924.3		c.441C>G	p.His147Gln	missense	Exon 4 of 5	NP_620279.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
GAMT	ENST00000252288.8	TSL:1 MANE Select	c.441C>G	p.His147Gln	missense	Exon 4 of 6	ENSP00000252288.1
GAMT	ENST00000447102.8	TSL:2	c.441C>G	p.His147Gln	missense	Exon 4 of 5	ENSP00000403536.2
GAMT	ENST00000640762.1	TSL:5	c.372C>G	p.His124Gln	missense	Exon 4 of 6	ENSP00000492031.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

BayesDel_addAF

Pathogenic

0.20

BayesDel_noAF

Uncertain

0.050

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.75

Eigen

Uncertain

0.36

Eigen_PC

Uncertain

0.29

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.87

M_CAP

Pathogenic

0.41

MetaRNN

Uncertain

0.72

MetaSVM

Uncertain

0.32

MutationAssessor

Uncertain

2.7

PhyloP100

2.0

PrimateAI

Uncertain

0.63

PROVEAN

Uncertain

-4.2

REVEL

Pathogenic

0.72

Sift

Uncertain

0.010

Sift4G

Benign

0.29

Polyphen

1.0

Vest4

0.77

MutPred

0.36

Loss of disorder (P = 0.1422)

MVP

0.95

MPC

0.63

ClinPred

0.98

GERP RS

3.4

Varity_R

0.84

gMVP

0.69

Mutation Taster

=8/92

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over