19-1399896-G-T

Variant names:

• chr19-1399896-G-T
• rs1441030187
• NM_000156.6:c.224C>A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Moderate

The NM_000156.6(GAMT):​c.224C>A​(p.Ala75Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,456,236 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A75V) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: GAMT NM_000156.6 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.88

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 Pathogenic. Variant got 10 ACMG points.

• PM1: In a helix (size 5) in uniprot entity GAMT_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_000156.6
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-1399896-G-A is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.897
• PP5: Variant 19-1399896-G-T is Pathogenic according to our data. Variant chr19-1399896-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3384380.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GAMT	NM_000156.6	c.224C>A	p.Ala75Glu	missense_variant	Exon 2 of 6	ENST00000252288.8	NP_000147.1
GAMT	NM_138924.3	c.224C>A	p.Ala75Glu	missense_variant	Exon 2 of 5		NP_620279.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GAMT	ENST00000252288.8	c.224C>A	p.Ala75Glu	missense_variant	Exon 2 of 6	1	NM_000156.6	ENSP00000252288.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1456236 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 723922

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.01e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Jun 03, 2024

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

A different missense change at this residue (A75V) has been reported pathogenic in the published literature and at GeneDx in association with GAMT-related disorder; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 34974949, 24415674) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.85	D;.;.
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	D;D;D
M_CAP	Pathogenic	0.44	D
MetaRNN	Pathogenic	0.90	D;D;D
MetaSVM	Uncertain	0.67	D
MutationAssessor	Pathogenic	3.2	M;.;M
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-3.2	D;.;D
REVEL	Pathogenic	0.82
Sift	Uncertain	0.0020	D;.;T
Sift4G	Uncertain	0.020	D;.;D
Polyphen		1.0	D;.;.
Vest4		0.97
MutPred		0.64		Gain of disorder (P = 0.0364);.;Gain of disorder (P = 0.0364);
MVP		0.94
MPC		0.69
ClinPred		0.98	D
GERP RS		3.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.86
gMVP		0.96

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1441030187; hg19: chr19-1399895;