rs771827261

chr19-1399548-T-Achr19-1399548-T-Cchr19-1399548-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_000156.6(GAMT):c.367A>T(p.Thr123Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,822 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T123A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: GAMT NM_000156.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.92

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 3 ACMG points.

• PM1: In a domain RMT2 (size 223) in uniprot entity GAMT_HUMAN there are 69 pathogenic changes around while only 17 benign (80%) in NM_000156.6
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3038543).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GAMT	NM_000156.6	c.367A>T	p.Thr123Ser	missense_variant	3/6	ENST00000252288.8
GAMT	NM_138924.3	c.367A>T	p.Thr123Ser	missense_variant	3/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GAMT	ENST00000252288.8	c.367A>T	p.Thr123Ser	missense_variant	3/6	1	NM_000156.6	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000402 AC: 1 AN: 248736 Hom.: 0 AF XY: 0.00000741 AC XY: 1 AN XY: 134890

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000891

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460822 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726610

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Uncertain	0.040	T
BayesDel_noAF	Benign	-0.18
Cadd	Benign	19
Dann	Benign	0.97
DEOGEN2	Benign	0.35	T;.;.
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.15
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.78	T;T;T
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.30	T;T;T
MetaSVM	Benign	-0.44	T
MutationAssessor	Benign	1.9	L;.;L
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.96	N;.;N
REVEL	Uncertain	0.39
Sift	Benign	0.54	T;.;T
Sift4G	Benign	0.61	T;.;T
Polyphen		0.12	B;.;.
Vest4		0.57
MutPred		0.28		Gain of disorder (P = 0.0618);.;Gain of disorder (P = 0.0618);
MVP		0.85
MPC		0.13
ClinPred		0.28	T
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.56
gMVP		0.49

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs771827261; hg19: chr19-1399547;