rs17851582

Variant names:

• chr19-1397444-G-A
• rs17851582
• NM_000156.6:c.626C>T

Your query was ambiguous. Multiple possible variants found:

• chr19-1397444-G-A
• chr19-1397444-G-T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BS2 BA1 BP4

This summary comes from the ClinGen Evidence Repository: The NM_000156.6:c.626C>T variant in GAMT is a missense variant predicted to result in the substitution of threonine for methionine at amino acid 209 (p.Thr209Met). The highest continental population minor allele frequency in gnomAD v2.1.1 is 0.09656 (12354/ 127944 alleles) in the European non-Finnish population, which is higher than the ClinGen CCDS VCEP’s threshold for BA1 (>0.003), and therefore meets this criterion (BA1). There are 987 homozygotes in gnomAD v2.1.1. Given that GAMT deficiency has an early onset, this data supports that the variant does not cause the condition (BS2). The computational predictor REVEL gives a score of 0.313 which is below the threshold of 0.5, evidence that does not predict a damaging effect on GAMT function (BP4). It has been previously reported in a large Italian family (PMID:12468279), where it did not segregate with AGAT deficiency, including being found in the homozygous state in the father, who was asymptomatic and had normal GAMT enzyme activity. It has also been found in presumed cis with the c.160G>C (p.Ala54Pro) variant in a patient with severe GAMT deficiency, as both parents were heterozygous for both the c.160G>C variant and c.626C>T variant and the patient was homozygous for both variants (PMID:15108290). In this publication (PMID:15108290), the c.626C>T was classified as a benign polymorphism due to its high frequency in a group of control individuals screened. It is noted in ClinVar (Variation ID: 21068). In summary, this variant meets the criteria to be classified as benign for GAMT deficiency. GAMT-specific ACMG/AMP codes met, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes VCEP (Specifications Version 1.1.0): BA1, BS2, BP4.(Classification approved by the ClinGen CCDS VCEP on June 6, 2022). LINK:https://erepo.genome.network/evrepo/ui/classification/CA288884/MONDO:0012999/026

• Frequency:
  • Genomes: 𝑓 0.069 (479 hom., cov: 33)
  • Exomes 𝑓: 0.096 (7395 hom.)
• Consequence: GAMT NM_000156.6 missense
• Clinical Significance: Benign reviewed by expert panel B:16 O:1
• Conservation: PhyloP100: 2.84
• Publications: 24 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: Orphanet, G2P, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: For more information check the summary or visit ClinGen Evidence Repository.
• BS2: 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.626C>T	p.Thr209Met	missense	Exon 6 of 6	NP_000147.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GAMT	ENST00000252288.8	TSL:1 MANE Select	c.626C>T	p.Thr209Met	missense	Exon 6 of 6	ENSP00000252288.1
	GAMT	ENST00000902474.1		c.896C>T	p.Thr299Met	missense	Exon 6 of 6	ENSP00000572533.1
	GAMT	ENST00000902472.1		c.629C>T	p.Thr210Met	missense	Exon 6 of 6	ENSP00000572531.1

Frequencies

GnomAD3 genomes AF: 0.0695 AC: 10583 AN: 152176 Hom.: 479 Cov.: 33

Gnomad AFR AF: 0.0180

Gnomad AMI AF: 0.0669

Gnomad AMR AF: 0.0618

Gnomad ASJ AF: 0.0602

Gnomad EAS AF: 0.000768

Gnomad SAS AF: 0.0656

Gnomad FIN AF: 0.102

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.104

Gnomad OTH AF: 0.0670

GnomAD2 exomes AF: 0.0763 AC: 18891 AN: 247438 AF XY: 0.0774

Gnomad AFR exome AF: 0.0163

Gnomad AMR exome AF: 0.0784

Gnomad ASJ exome AF: 0.0651

Gnomad EAS exome AF: 0.000218

Gnomad FIN exome AF: 0.102

Gnomad NFE exome AF: 0.0951

Gnomad OTH exome AF: 0.0840

GnomAD4 exome AF: 0.0962 AC: 140321 AN: 1458180 Hom.: 7395 Cov.: 32 AF XY: 0.0958 AC XY: 69495 AN XY: 725482

African (AFR) AF: 0.0140 AC: 470 AN: 33476

American (AMR) AF: 0.0762 AC: 3408 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.0679 AC: 1774 AN: 26124

East Asian (EAS) AF: 0.000428 AC: 17 AN: 39694

South Asian (SAS) AF: 0.0693 AC: 5979 AN: 86258

European-Finnish (FIN) AF: 0.104 AC: 5210 AN: 49912

Middle Eastern (MID) AF: 0.0395 AC: 228 AN: 5768

European-Non Finnish (NFE) AF: 0.106 AC: 117763 AN: 1111880

Other (OTH) AF: 0.0907 AC: 5472 AN: 60356

GnomAD4 genome AF: 0.0695 AC: 10579 AN: 152294 Hom.: 479 Cov.: 33 AF XY: 0.0674 AC XY: 5018 AN XY: 74468

African (AFR) AF: 0.0179 AC: 744 AN: 41564

American (AMR) AF: 0.0617 AC: 944 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0602 AC: 209 AN: 3472

East Asian (EAS) AF: 0.000770 AC: 4 AN: 5194

South Asian (SAS) AF: 0.0657 AC: 317 AN: 4828

European-Finnish (FIN) AF: 0.102 AC: 1080 AN: 10626

Middle Eastern (MID) AF: 0.0408 AC: 12 AN: 294

European-Non Finnish (NFE) AF: 0.104 AC: 7068 AN: 67992

Other (OTH) AF: 0.0663 AC: 140 AN: 2112

Alfa AF: 0.0861 Hom.: 956

Bravo AF: 0.0640

TwinsUK AF: 0.0984 AC: 365

ALSPAC AF: 0.106 AC: 410

ESP6500AA AF: 0.0204 AC: 90

ESP6500EA AF: 0.0972 AC: 836

ExAC AF: 0.0746 AC: 9036

Asia WGS AF: 0.0260 AC: 92 AN: 3478

EpiCase AF: 0.0913

EpiControl AF: 0.0865

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	5	Deficiency of guanidinoacetate methyltransferase (6)
-	-	5	not specified (5)
-	-	2	not provided (2)
-	-	1	Cerebral creatine deficiency syndrome (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	Leigh syndrome (1)
-	-	1	Mitochondrial complex I deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.42	T
Eigen	Benign	0.17
Eigen_PC	Benign	0.084
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.71	T
MetaRNN	Benign	0.0026	T
MetaSVM	Benign	-0.67	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		2.8
PROVEAN	Benign	-1.8	N
REVEL	Uncertain	0.31
Sift	Benign	0.19	T
Sift4G	Uncertain	0.036	D
Polyphen		1.0	D
Vest4		0.056
ClinPred		0.025	T
GERP RS		5.1
Varity_R		0.20
Mutation Taster		=87/13	polymorphism (auto)

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: rs17851582; hg19: chr19-1397443; COSMIC: COSV52041101; COSMIC: COSV52041101;