chr19-1397400-C-T

Position:

• chr19-1397400-C-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 1P and 2B. PM2_Supporting BS3_Supporting BP4

This summary comes from the ClinGen Evidence Repository: The NM_000156.6:c.670G>A variant in GAMT is a missense variant that is predicted to result in the substitution of alanine by threonine at amino acid 224 (p.Ala224Thr). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00034 (12/35338 alleles) in the Latino population, which is lower than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.0004), meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.147 which is below the threshold of 0.5, evidence that does not predict a damaging effect on GAMT function (BP4). Expression of the variant in GAMT-deficient fibroblasts showed that it resulted in similar GAMT enzymatic activity to wild-type (BS3_Supporting). There is a ClinVar entry for this variant (Variant ID: 205593). In summary, this variant meets the criteria to be classified as likely benign for GAMT deficiency. Although there are both pathogenic and benign types of evidence for this variant, the pathogenic evidence is not considered inconsistent with the final classification. GAMT-specific ACMG/AMP criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): PM2_Supporting, BS3_Supporting, BP4.(Classification approved by the ClinGen CCDS VCEP on February 23, 2023). LINK:https://erepo.genome.network/evrepo/ui/classification/CA314830/MONDO:0012999/026

• Frequency:
  • Genomes: 𝑓 0.000085 (0 hom., cov: 33)
  • 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: 0.304

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 Likely_benign. Variant got -1 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GAMT	NM_000156.6	c.670G>A	p.Ala224Thr	missense_variant	6/6	ENST00000252288.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GAMT	ENST00000252288.8	c.670G>A	p.Ala224Thr	missense_variant	6/6	1	NM_000156.6	P1
GAMT	ENST00000640762.1	c.601G>A	p.Ala201Thr	missense_variant	6/6	5
GAMT	ENST00000640164.1	n.503G>A		non_coding_transcript_exon_variant	4/4	2

Frequencies

GnomAD3 genomes AF: 0.0000854 AC: 13 AN: 152186 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000965

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: 0.000132

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000209 AC: 52 AN: 248212 Hom.: 0 AF XY: 0.000230 AC XY: 31 AN XY: 134766

Gnomad AFR exome AF: 0.0000625

Gnomad AMR exome AF: 0.000348

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000545

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000276

Gnomad OTH exome AF: 0.000330

GnomAD4 exome AF: 0.000175 AC: 256 AN: 1460164 Hom.: 1 Cov.: 30 AF XY: 0.000193 AC XY: 140 AN XY: 726402

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.000268

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000267

Gnomad4 FIN exome AF: 0.0000193

Gnomad4 NFE exome AF: 0.000181

Gnomad4 OTH exome AF: 0.0000828

GnomAD4 genome AF: 0.0000854 AC: 13 AN: 152186 Hom.: 0 Cov.: 33 AF XY: 0.0000404 AC XY: 3 AN XY: 74342

Gnomad4 AFR AF: 0.0000965

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: 0.000132

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000280 Hom.: 0

Bravo AF: 0.000181

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000264 AC: 32

EpiCase AF: 0.000218

EpiControl AF: 0.000533

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:5 Benign:2

Revision: reviewed by expert panel

Submissions by phenotype

not provided Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 22, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 11, 2019	This variant is associated with the following publications: (PMID: 26319512) -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 09, 2019	- -

Deficiency of guanidinoacetate methyltransferase Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	May 09, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Likely benign, reviewed by expert panel	curation	ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel, ClinGen	Feb 09, 2023	The NM_000156.6:c.670G>A variant in GAMT is a missense variant that is predicted to result in the substitution of alanine by threonine at amino acid 224 (p.Ala224Thr). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00034 (12/35338 alleles) in the Latino population, which is lower than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.0004), meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.147 which is below the threshold of 0.5, evidence that does not predict a damaging effect on GAMT function (BP4). Expression of the variant in GAMT-deficient fibroblasts showed that it resulted in similar GAMT enzymatic activity to wild-type (BS3_Supporting). There is a ClinVar entry for this variant (Variant ID: 205593). In summary, this variant meets the criteria to be classified as likely benign for GAMT deficiency. Although there are both pathogenic and benign types of evidence for this variant, the pathogenic evidence is not considered inconsistent with the final classification. GAMT-specific ACMG/AMP criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): PM2_Supporting, BS3_Supporting, BP4. (Classification approved by the ClinGen CCDS VCEP on February 23, 2023). -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 24, 2022

The c.670G>A (p.A224T) alteration is located in exon 6 (coding exon 6) of the GAMT gene. This alteration results from a G to A substitution at nucleotide position 670, causing the alanine (A) at amino acid position 224 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Cerebral creatine deficiency syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 25, 2022

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 224 of the GAMT protein (p.Ala224Thr). This variant is present in population databases (rs141471799, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with GAMT-related conditions. ClinVar contains an entry for this variant (Variation ID: 205593). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt GAMT protein function. Experimental studies have shown that this missense change does not substantially affect GAMT function (PMID: 26319512). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	14
DANN	Uncertain	0.99
DEOGEN2	Benign	0.27	T;.
Eigen	Benign	-0.95
Eigen_PC	Benign	-0.88
FATHMM_MKL	Benign	0.46	N
LIST_S2	Benign	0.78	T;T
M_CAP	Benign	0.046	D
MetaRNN	Benign	0.063	T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.36	N;.
MutationTaster	Benign	0.79	N
PROVEAN	Benign	-0.34	N;.
REVEL	Benign	0.15
Sift	Benign	0.42	T;.
Sift4G	Benign	0.22	T;.
Polyphen		0.0030	B;.
Vest4		0.069
MVP		0.67
ClinPred		0.026	T
GERP RS		-3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.083

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: rs141471799; hg19: chr19-1397399;