19-1399149-T-C

Position:

• chr19-1399149-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 5P and 3B. BP7 PM2_Supporting BP2 BP4 PP4_Strong

This summary comes from the ClinGen Evidence Repository: The NM_000156.6:c.438A>G (p.Thr146=) variant in GAMT is a synonymous variant in exon 4 that is predicted to not impact splicing by SpliceAI and VarSeak, and the nucleotide is not highly conserved (BP4, BP7). This variant has been previously reported in an individual with GAMT deficiency who had significantly decreased creatine peak on MRS (PMID:7808840) and GAMT activity <0.1% versus normal in fibroblasts (PMID:11978605) (PP4_Strong). Familial analysis showed that this individual harbored the variant in cis with c.299_311dup (also known as c.309ins13; pathogenic based on classification by the ClinGen CCDS VCEP) and had co-inherited the variants from his unaffected mother (BP2); he was also heterozygous for the pathogenic variant c.327G>A, inherited from his father. Of note, his unaffected brother also harbored the two maternally co-inherited (c.438A>G and c.309ins13) variants. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00004 (4/ 113532 alleles) in the European non-Finnish population, which is lower than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.0004), meeting this criterion (PM2_Supporting). It is noted in ClinVar (ID 21066). In summary, this variant meets the criteria to be classified as a variant of 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): PP4_Strong, PM2_Supporting, BP2, BP4, BP7.(Classification approved by the ClinGen CCDS VCEP on June 6, 2022). LINK:https://erepo.genome.network/evrepo/ui/classification/CA341572/MONDO:0012999/026

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000025 (0 hom.)
• Consequence: GAMT NM_000156.6 synonymous
• Clinical Significance: Uncertain significance reviewed by expert panel U:2 B:1 O:1
• Conservation: PhyloP100: -4.24

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.
• BP2: For more information check the summary or visit ClinGen Evidence Repository.
• BP4: For more information check the summary or visit ClinGen Evidence Repository.
• BP7: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GAMT	NM_000156.6	c.438A>G	p.Thr146Thr	synonymous_variant	4/6	ENST00000252288.8	NP_000147.1
GAMT	NM_138924.3	c.438A>G	p.Thr146Thr	synonymous_variant	4/5		NP_620279.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GAMT	ENST00000252288.8	c.438A>G	p.Thr146Thr	synonymous_variant	4/6	1	NM_000156.6	ENSP00000252288.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152150 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000199 AC: 5 AN: 251204 Hom.: 0 AF XY: 0.0000294 AC XY: 4 AN XY: 135898

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000246 AC: 36 AN: 1461480 Hom.: 0 Cov.: 34 AF XY: 0.0000206 AC XY: 15 AN XY: 727046

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000297

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152150 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74316

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2 Benign:1 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Deficiency of guanidinoacetate methyltransferase Uncertain:2 Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Uncertain significance, reviewed by expert panel	curation	ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel, ClinGen	Jun 06, 2022	The NM_000156.6:c.438A>G (p.Thr146=) variant in GAMT is a synonymous variant in exon 4 that is predicted to not impact splicing by SpliceAI and VarSeak, and the nucleotide is not highly conserved (BP4, BP7). This variant has been previously reported in an individual with GAMT deficiency who had significantly decreased creatine peak on MRS (PMID: 7808840) and GAMT activity <0.1% versus normal in fibroblasts (PMID: 11978605) (PP4_Strong). Familial analysis showed that this individual harbored the variant in cis with c.299_311dup (also known as c.309ins13; pathogenic based on classification by the ClinGen CCDS VCEP) and had co-inherited the variants from his unaffected mother (BP2); he was also heterozygous for the pathogenic variant c.327G>A, inherited from his father. Of note, his unaffected brother also harbored the two maternally co-inherited (c.438A>G and c.309ins13) variants. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00004 (4/ 113532 alleles) in the European non-Finnish population, which is lower than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.0004), meeting this criterion (PM2_Supporting). It is noted in ClinVar (ID 21066). In summary, this variant meets the criteria to be classified as a variant of 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): PP4_Strong, PM2_Supporting, BP2, BP4, BP7. (Classification approved by the ClinGen CCDS VCEP on June 6, 2022). -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Aug 14, 2018	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Cerebral creatine deficiency syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 20, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.67
DANN	Benign	0.71

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: rs80338733; hg19: chr19-1399148;