rs77168423

chr19-1399938-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 5P and 5B. PM1 PM5 PP3 BP6 BS1

The NM_000156.6(GAMT):c.182G>A(p.Gly61Glu) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000334 in 1,605,756 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G61R) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00014 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00036 (5 hom.)
• Consequence: GAMT NM_000156.6 missense, splice_region
• Scores: Splicing: ADA: 0.9948
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 7.58

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 Uncertain_significance. Variant got 0 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_000156.6
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-1401296-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1098275.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• BP6: Variant 19-1399938-C-T is Benign according to our data. Variant chr19-1399938-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 328350.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=1}.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000138 (21/152322) while in subpopulation EAS AF= 0.00406 (21/5178). AF 95% confidence interval is 0.00272. There are 1 homozygotes in gnomad4. There are 17 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GAMT	NM_000156.6	c.182G>A	p.Gly61Glu	missense_variant, splice_region_variant	2/6	ENST00000252288.8
GAMT	NM_138924.3	c.182G>A	p.Gly61Glu	missense_variant, splice_region_variant	2/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GAMT	ENST00000252288.8	c.182G>A	p.Gly61Glu	missense_variant, splice_region_variant	2/6	1	NM_000156.6	P1
GAMT	ENST00000447102.8	c.182G>A	p.Gly61Glu	missense_variant, splice_region_variant	2/5	2
GAMT	ENST00000640762.1	c.113G>A	p.Gly38Glu	missense_variant, splice_region_variant	2/6	5

Frequencies

GnomAD3 genomes AF: 0.000138 AC: 21 AN: 152206 Hom.: 1 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: 0.00405

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000116 AC: 27 AN: 232624 Hom.: 0 AF XY: 0.0000869 AC XY: 11 AN XY: 126550

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00142

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000351

GnomAD4 exome AF: 0.000355 AC: 516 AN: 1453434 Hom.: 5 Cov.: 33 AF XY: 0.000352 AC XY: 254 AN XY: 722390

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0129

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.000133

GnomAD4 genome AF: 0.000138 AC: 21 AN: 152322 Hom.: 1 Cov.: 32 AF XY: 0.000228 AC XY: 17 AN XY: 74482

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00406

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000231 Hom.: 0

Bravo AF: 0.0000227

ExAC AF: 0.000199 AC: 24

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Deficiency of guanidinoacetate methyltransferase Uncertain:1 Benign:1

Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 07, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jun 10, 2020

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Cerebral creatine deficiency syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jun 03, 2022

This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 61 of the GAMT protein (p.Gly61Glu). This variant is present in population databases (rs77168423, gnomAD 0.2%). 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: 328350). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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	Pathogenic	0.61
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Uncertain	0.030
Cadd	Pathogenic	34
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.77	D;.;.
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.88	D;T;D
M_CAP	Pathogenic	0.45	D
MetaRNN	Benign	0.042	T;T;T
MetaSVM	Uncertain	0.59	D
MutationAssessor	Uncertain	2.0	M;.;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-6.9	D;.;D
REVEL	Pathogenic	0.76
Sift	Uncertain	0.0020	D;.;T
Sift4G	Pathogenic	0.0	D;.;D
Polyphen		1.0	D;.;.
Vest4		0.74
MVP		0.97
MPC		0.37
ClinPred		0.32	T
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.92
gMVP		0.64

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Pathogenic	0.86
SpliceAI score (max)		0.13		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: rs77168423; hg19: chr19-1399937;