rs200833152

Variant names:

• chr19-1401398-A-G
• rs200833152
• NM_000156.6:c.79T>C

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BA1 BS3_Supporting

This summary comes from the ClinGen Evidence Repository: NM_000156.6:c.79T>C variant in GAMT is a missense variant that is predicted to result in the substitution of tyrosine by histidine at amino acid 27 (p.Tyr27His). This variant was identified in the homozygous state in an individual with normal GAMT enzyme activity in fibroblasts (PMID:24415674). The variant is present in gnomAD v2.1.1. at a maximum population frequency of 0.00471 (>0.003, cutoff for BA1) and found in the homozygous state in 2 individuals in gnomAD v2.1.1 (BA1). In fibroblasts, overexpressing the GAMT c.79T>C (p.Tyr27His) variant, restored GAMT activity to similar levels as the wild-type GAMT transfection (PMID:24415674)(BS3_Supporting). There is a ClinVar entry for this variant (Variation ID: 167131). In summary, this variant meets the criteria to be classified as benign for GAMT deficiency. GAMT-specific ACMG/AMP criteria met, based on the specifications of the ClinGen Cerebral Creatine Deficiencies VCEP (Specifications Version 1.1.0): BA1, BS3_Supporting.(Classification approved by the ClinGen CCDS VCEP on February 8, 2023). LINK:https://erepo.genome.network/evrepo/ui/classification/CA295620/MONDO:0012999/026

• Frequency:
  • Genomes: 𝑓 0.0034 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0046 (18 hom.)
• Consequence: GAMT NM_000156.6 missense
• Clinical Significance: Benign reviewed by expert panel P:1 U:3 B:15 O:1
• Conservation: PhyloP100: 7.08
• 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

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

Our verdict: Benign. The variant received -9 ACMG points.

• BS3: For more information check the summary or visit ClinGen Evidence Repository.
• BA1: 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.79T>C	p.Tyr27His	missense	Exon 1 of 6	NP_000147.1	Q14353-1
	GAMT	NM_138924.3		c.79T>C	p.Tyr27His	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.79T>C	p.Tyr27His	missense	Exon 1 of 6	ENSP00000252288.1	Q14353-1
	GAMT	ENST00000902474.1		c.79T>C	p.Tyr27His	missense	Exon 1 of 6	ENSP00000572533.1
	GAMT	ENST00000447102.8	TSL:2	c.79T>C	p.Tyr27His	missense	Exon 1 of 5	ENSP00000403536.2	Q14353-2

Frequencies

GnomAD3 genomes AF: 0.00339 AC: 516 AN: 152024 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00159

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00582

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000566

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00494

Gnomad OTH AF: 0.00766

GnomAD2 exomes AF: 0.00282 AC: 245 AN: 86858 AF XY: 0.00268

Gnomad AFR exome AF: 0.00160

Gnomad AMR exome AF: 0.00477

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000970

Gnomad NFE exome AF: 0.00444

Gnomad OTH exome AF: 0.00376

GnomAD4 exome AF: 0.00456 AC: 5989 AN: 1313380 Hom.: 18 Cov.: 31 AF XY: 0.00438 AC XY: 2834 AN XY: 647264

African (AFR) AF: 0.00130 AC: 35 AN: 26962

American (AMR) AF: 0.00455 AC: 123 AN: 27058

Ashkenazi Jewish (ASJ) AF: 0.000430 AC: 10 AN: 23234

East Asian (EAS) AF: 0.00 AC: 0 AN: 28760

South Asian (SAS) AF: 0.00 AC: 0 AN: 70922

European-Finnish (FIN) AF: 0.00136 AC: 45 AN: 33100

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4324

European-Non Finnish (NFE) AF: 0.00532 AC: 5557 AN: 1044644

Other (OTH) AF: 0.00403 AC: 219 AN: 54376

GnomAD4 genome AF: 0.00339 AC: 516 AN: 152132 Hom.: 4 Cov.: 32 AF XY: 0.00333 AC XY: 248 AN XY: 74374

African (AFR) AF: 0.00159 AC: 66 AN: 41532

American (AMR) AF: 0.00582 AC: 89 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5140

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.000566 AC: 6 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00495 AC: 336 AN: 67942

Other (OTH) AF: 0.00758 AC: 16 AN: 2110

Alfa AF: 0.00519 Hom.: 1

Bravo AF: 0.00357

TwinsUK AF: 0.00485 AC: 18

ALSPAC AF: 0.00623 AC: 24

ESP6500AA AF: 0.00123 AC: 5

ESP6500EA AF: 0.00239 AC: 19

ExAC AF: 0.00165 AC: 164

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	1	5	not specified (6)
-	1	4	not provided (5)
1	1	2	Deficiency of guanidinoacetate methyltransferase (4)
-	-	1	Cerebral creatine deficiency syndrome (1)
-	-	1	GAMT-related disorder (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	Intellectual disability (1)
-	-	-	Guanidinoacetate methyltransferase (GAMT) deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.79
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Uncertain	0.070
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.84	D
Eigen	Uncertain	0.35
Eigen_PC	Benign	0.18
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.78	T
M_CAP	Pathogenic	0.68	D
MetaRNN	Benign	0.0093	T
MetaSVM	Uncertain	0.63	D
MutationAssessor	Pathogenic	3.0	M
PhyloP100		7.1
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-2.5	N
REVEL	Pathogenic	0.65
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.52
MVP		0.91
MPC		0.72
ClinPred		0.066	T
GERP RS		3.1
PromoterAI		-0.28	Neutral
Varity_R		0.62
gMVP		0.80
Mutation Taster		=85/15	polymorphism

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: rs200833152; hg19: chr19-1401397;