rs776498025

Variant names:

• chr19-1401455-G-T
• rs776498025
• NM_000156.6:c.22C>A

Variant summary

Our verdict is Uncertain significance. The variant received -1 ACMG points: 1P and 2B. PM2_Supporting BS3_Supporting BP4

This summary comes from the ClinGen Evidence Repository: The NM_000156.6:c.22C>A variant in GAMT is a missense variant that is predicted to result in the substitution of proline by threonine at amino acid 8 (p.Pro8Thr). One patient, who is heterozygous for the variant, has been reported. This individual, who presented with severe global develpomental delay, hypotonia, and intractable seizures, died at 11 months of age. Urine and plasma guanidinoacetate were elevated 2.5 and 1.8 times, respectively. However, on 1H-MRS, creatine peak was about 90% of normal, marginally low, which was not suggestive of GAMT deficiency(PMID:24415674) (PP4 not applied). GAA-deficient fibroblasts overexpressing the c.22C>A (p.Pro8Thr) variant showed similar GAMT enzyme activity as those transfected with wild-type cDNA (PMID:24415674) (BS3_Supporting). The computational predictor REVEL gives a score of 0.479 which is below the threshold of 0.5, evidence that does not predict a damaging effect on GAMT function (BP4). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00023 (7/30820 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). There is a ClinVar entry for this variant (Variation ID: 205598). In summary, this variant meets the criteria to be classified as a variant of uncertain significance 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): BS3_Supporting, BP4, PM2_Supporting. Although this variant meets criteria for a classification of Variant of Uncertain Significance, the ClinGen Cerebral Creatine Deficiencies VCEP considers this variant suspicious for Likely Benign. Future literature may warrant a reclassification of this variant. LINK:https://erepo.genome.network/evrepo/ui/classification/CA314840/MONDO:0012999/026

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00018 (1 hom.)
• Consequence: GAMT NM_000156.6 missense
• Clinical Significance: Likely benign reviewed by expert panel U:5 B:2
• Conservation: PhyloP100: 7.17
• Publications: 3 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: Uncertain_significance. The variant received -1 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• BP4: For more information check the summary or visit ClinGen Evidence Repository.
• BS3: 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.22C>A	p.Pro8Thr	missense	Exon 1 of 6	NP_000147.1	Q14353-1
	GAMT	NM_138924.3		c.22C>A	p.Pro8Thr	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.22C>A	p.Pro8Thr	missense	Exon 1 of 6	ENSP00000252288.1	Q14353-1
	GAMT	ENST00000902474.1		c.22C>A	p.Pro8Thr	missense	Exon 1 of 6	ENSP00000572533.1
	GAMT	ENST00000447102.8	TSL:2	c.22C>A	p.Pro8Thr	missense	Exon 1 of 5	ENSP00000403536.2	Q14353-2

Frequencies

GnomAD3 genomes AF: 0.000171 AC: 26 AN: 152042 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: 0.0000945

Gnomad MID AF: 0.00955

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.000144 AC: 6 AN: 41720 AF XY: 0.000161

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: 0.000323

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000177 AC: 219 AN: 1239768 Hom.: 1 Cov.: 31 AF XY: 0.000165 AC XY: 100 AN XY: 605594

African (AFR) AF: 0.00 AC: 0 AN: 25310

American (AMR) AF: 0.000217 AC: 4 AN: 18424

Ashkenazi Jewish (ASJ) AF: 0.0000498 AC: 1 AN: 20084

East Asian (EAS) AF: 0.00 AC: 0 AN: 27432

South Asian (SAS) AF: 0.0000679 AC: 4 AN: 58924

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 30606

Middle Eastern (MID) AF: 0.00222 AC: 8 AN: 3608

European-Non Finnish (NFE) AF: 0.000188 AC: 189 AN: 1004506

Other (OTH) AF: 0.000256 AC: 13 AN: 50874

GnomAD4 genome AF: 0.000164 AC: 25 AN: 152150 Hom.: 0 Cov.: 32 AF XY: 0.000108 AC XY: 8 AN XY: 74382

African (AFR) AF: 0.0000241 AC: 1 AN: 41552

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5156

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.0000945 AC: 1 AN: 10586

Middle Eastern (MID) AF: 0.00685 AC: 2 AN: 292

European-Non Finnish (NFE) AF: 0.000250 AC: 17 AN: 67952

Other (OTH) AF: 0.00189 AC: 4 AN: 2114

Alfa AF: 0.000214 Hom.: 0

Bravo AF: 0.0000945

ExAC AF: 0.0000457 AC: 2

Asia WGS AF: 0.000290 AC: 1 AN: 3466

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	3	1	Deficiency of guanidinoacetate methyltransferase (4)
-	1	-	Cerebral creatine deficiency syndrome (1)
-	1	-	Inborn genetic diseases (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.066	T
BayesDel_noAF	Uncertain	-0.040
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.43	T
Eigen	Benign	0.010
Eigen_PC	Benign	0.078
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.69	T
M_CAP	Pathogenic	0.94	D
MetaRNN	Benign	0.41	T
MetaSVM	Uncertain	0.41	D
MutationAssessor	Uncertain	2.5	M
PhyloP100		7.2
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-1.7	N
REVEL	Uncertain	0.48
Sift	Benign	0.040	D
Sift4G	Uncertain	0.0090	D
Polyphen		0.041	B
Vest4		0.42
MVP		0.95
MPC		0.55
ClinPred		0.30	T
GERP RS		3.8
PromoterAI		0.19	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.46
gMVP		0.87
Mutation Taster		=63/37	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: rs776498025; hg19: chr19-1401454;