rs574164748

Positions:

• chr19-1401470-C-A
• chr19-1401470-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM1 PM2 BP4_Moderate BP6_Moderate

The NM_000156.6(GAMT):​c.7G>T​(p.Ala3Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000827 in 1,209,714 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 8.3e-7 (0 hom.)
• Consequence: GAMT NM_000156.6 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.157

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 chain Guanidinoacetate N-methyltransferase (size 234) in uniprot entity GAMT_HUMAN there are 37 pathogenic changes around while only 8 benign (82%) in NM_000156.6
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14780992).
• BP6: Variant 19-1401470-C-A is Benign according to our data. Variant chr19-1401470-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 205575.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GAMT	NM_000156.6	c.7G>T	p.Ala3Ser	missense_variant	1/6	ENST00000252288.8	NP_000147.1
GAMT	NM_138924.3	c.7G>T	p.Ala3Ser	missense_variant	1/5		NP_620279.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GAMT	ENST00000252288.8	c.7G>T	p.Ala3Ser	missense_variant	1/6	1	NM_000156.6	ENSP00000252288	P1
GAMT	ENST00000447102.8	c.7G>T	p.Ala3Ser	missense_variant	1/5	2		ENSP00000403536
GAMT	ENST00000640762.1	c.7G>T	p.Ala3Ser	missense_variant	1/6	5		ENSP00000492031

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 8.27e-7 AC: 1 AN: 1209714 Hom.: 0 Cov.: 31 AF XY: 0.00000170 AC XY: 1 AN XY: 588214

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: 0.0000187

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 08, 2013

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.020	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	5.8
DANN	Benign	0.95
DEOGEN2	Benign	0.32	T;.;.
Eigen	Benign	-0.92
Eigen_PC	Benign	-0.97
FATHMM_MKL	Benign	0.081	N
LIST_S2	Benign	0.35	T;T;T
M_CAP	Pathogenic	0.89	D
MetaRNN	Benign	0.15	T;T;T
MetaSVM	Benign	-0.40	T
MutationAssessor	Benign	0.14	N;.;N
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-0.63	N;.;N
REVEL	Benign	0.22
Sift	Benign	0.43	T;.;T
Sift4G	Benign	0.32	T;.;T
Polyphen		0.0030	B;.;.
Vest4		0.14
MutPred		0.079		Gain of glycosylation at A3 (P = 0.0018);Gain of glycosylation at A3 (P = 0.0018);Gain of glycosylation at A3 (P = 0.0018);
MVP		0.80
MPC		0.14
ClinPred		0.11	T
GERP RS		1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.071
gMVP		0.45

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: rs574164748; hg19: chr19-1401469;