rs80338734

Variant names:

• chr19-1401418-C-A
• rs80338734
• NM_000156.6:c.59G>T

Your query was ambiguous. Multiple possible variants found:

• chr19-1401418-C-A
• chr19-1401418-C-G
• chr19-1401418-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM5 PP3 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_000156.6:c.59G>T variant in GAMT is a missense variant that is predicted to result in the substitution of tryptophan by leucine at amino acid 20 (p.Trp20Leu). To our knowledge, this variant has not been reported in individuals with GAMT deficiency and the result of functional studies are not available. The computational predictor REVEL gives a score of 0.804 which is above the threshold of 0.75, evidence that correlates with impact to GAMT function (PP3). Another missense variant, c.59G>C (p.Trp20Ser) (ClinVar Variation ID: 8303)) has been reported at the same amino acid position and has been classified as pathogenic for GAMT deficiency by the ClinGen CCDS VCEP (PM5). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 588631, 1 star review status). In summary, this variant meets the criteria to be classified as uncertain significance for GAMT deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 1.1.0): PM2_Supporting, PM5, PP3.(Classification approved by the ClinGen CCDS VCEP, Sept 12, 2023) LINK:https://erepo.genome.network/evrepo/ui/classification/CA402998326/MONDO:0012999/026

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: GAMT NM_000156.6 missense
• Clinical Significance: Uncertain significance reviewed by expert panel P:1 U:3
• Conservation: PhyloP100: 7.44
• Publications: 13 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: Ambry Genetics, Orphanet, G2P, ClinGen, Labcorp Genetics (formerly Invitae)

ACMG classification

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

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM5: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GAMT	NM_000156.6	MANE Select	c.59G>T	p.Trp20Leu	missense	Exon 1 of 6	NP_000147.1	Q14353-1
	GAMT	NM_138924.3		c.59G>T	p.Trp20Leu	missense	Exon 1 of 5	NP_620279.1	Q14353-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GAMT	ENST00000252288.8	TSL:1 MANE Select	c.59G>T	p.Trp20Leu	missense	Exon 1 of 6	ENSP00000252288.1	Q14353-1
	GAMT	ENST00000902474.1		c.59G>T	p.Trp20Leu	missense	Exon 1 of 6	ENSP00000572533.1
	GAMT	ENST00000447102.8	TSL:2	c.59G>T	p.Trp20Leu	missense	Exon 1 of 5	ENSP00000403536.2	Q14353-2

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152086 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000100 AC: 13 AN: 1296552 Hom.: 0 Cov.: 31 AF XY: 0.0000110 AC XY: 7 AN XY: 638052

African (AFR) AF: 0.000113 AC: 3 AN: 26520

American (AMR) AF: 0.0000399 AC: 1 AN: 25048

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22834

East Asian (EAS) AF: 0.00 AC: 0 AN: 28182

South Asian (SAS) AF: 0.0000435 AC: 3 AN: 69034

European-Finnish (FIN) AF: 0.0000308 AC: 1 AN: 32486

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4068

European-Non Finnish (NFE) AF: 0.00000483 AC: 5 AN: 1034812

Other (OTH) AF: 0.00 AC: 0 AN: 53568

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152086 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74292

African (AFR) AF: 0.0000241 AC: 1 AN: 41440

American (AMR) AF: 0.00 AC: 0 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5158

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 67994

Other (OTH) AF: 0.00 AC: 0 AN: 2084

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	1	-	Cerebral creatine deficiency syndrome (1)
-	1	-	Deficiency of guanidinoacetate methyltransferase (1)
1	-	-	Inborn genetic diseases (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	31
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.84	D
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.77	T
M_CAP	Pathogenic	0.88	D
MetaRNN	Pathogenic	0.86	D
MetaSVM	Uncertain	0.76	D
MutationAssessor	Pathogenic	3.1	M
PhyloP100		7.4
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-5.8	D
REVEL	Pathogenic	0.80
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.037	D
Polyphen		1.0	D
Vest4		0.72
MutPred		0.54		Loss of catalytic residue at W20 (P = 0.0221)
MVP		0.95
MPC		0.84
ClinPred		1.0	D
GERP RS		4.0
PromoterAI		-0.033	Neutral
Varity_R		0.94
gMVP		0.77
Mutation Taster		=4/96	disease causing (ClinVar)

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: rs80338734; hg19: chr19-1401417;