rs80338736

Variant names:

• chr19-1399808-T-TGGGGCCCAGTCCC
• rs80338736
• NM_000156.6:c.299_311dupGGGACTGGGCCCC

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_000156.6(GAMT):​c.299_311dupGGGACTGGGCCCC​(p.Arg105GlyfsTer26) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000999 in 1,572,142 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. P104P) has been classified as Uncertain significance. Variant results in nonsense mediated mRNA decay. The gene GAMT is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: GAMT NM_000156.6 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:14
• Conservation: PhyloP100: -0.826
• Publications: 5 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

Specifications for GAMT are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 19-1399808-T-TGGGGCCCAGTCCC is Pathogenic according to our data. Variant chr19-1399808-T-TGGGGCCCAGTCCC is described in ClinVar as Pathogenic. ClinVar VariationId is 8302.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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GAMT	NM_000156.6	MANE Select	c.299_311dupGGGACTGGGCCCC	p.Arg105GlyfsTer26	frameshift	Exon 2 of 6	NP_000147.1	Q14353-1
	GAMT	NM_138924.3		c.299_311dupGGGACTGGGCCCC	p.Arg105GlyfsTer26	frameshift	Exon 2 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.299_311dupGGGACTGGGCCCC	p.Arg105GlyfsTer26	frameshift	Exon 2 of 6	ENSP00000252288.1	Q14353-1
	GAMT	ENST00000902474.1		c.569_581dupGGGACTGGGCCCC	p.Arg195GlyfsTer26	frameshift	Exon 2 of 6	ENSP00000572533.1
	GAMT	ENST00000447102.8	TSL:2	c.299_311dupGGGACTGGGCCCC	p.Arg105GlyfsTer26	frameshift	Exon 2 of 5	ENSP00000403536.2	Q14353-2

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152070 Hom.: 0 Cov.: 32

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: 0.000103

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000539 AC: 10 AN: 185556 AF XY: 0.0000801

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000128

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000106 AC: 150 AN: 1420072 Hom.: 0 Cov.: 33 AF XY: 0.000104 AC XY: 73 AN XY: 702988

African (AFR) AF: 0.00 AC: 0 AN: 32538

American (AMR) AF: 0.0000257 AC: 1 AN: 38954

Ashkenazi Jewish (ASJ) AF: 0.0000394 AC: 1 AN: 25364

East Asian (EAS) AF: 0.00 AC: 0 AN: 37368

South Asian (SAS) AF: 0.00 AC: 0 AN: 81254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48426

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5718

European-Non Finnish (NFE) AF: 0.000130 AC: 142 AN: 1091664

Other (OTH) AF: 0.000102 AC: 6 AN: 58786

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152070 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74306

African (AFR) AF: 0.00 AC: 0 AN: 41396

American (AMR) AF: 0.00 AC: 0 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68000

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.000174 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
10	-	-	Deficiency of guanidinoacetate methyltransferase (10)
2	-	-	Cerebral creatine deficiency syndrome (2)
1	-	-	Inborn genetic diseases (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.83
Mutation Taster		=2/198	disease causing (ClinVar)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs80338736; hg19: chr19-1399807;