rs77168423

Variant names:

• chr19-1399938-C-A
• NM_000156.6:c.182G>T

Your query was ambiguous. Multiple possible variants found:

• chr19-1399938-C-A
• chr19-1399938-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP3

The NM_000156.6(GAMT):​c.182G>T​(p.Gly61Val) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,453,432 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: GAMT NM_000156.6 missense, splice_region
• Scores: Splicing: ADA: 0.9991
• Clinical Significance: Not reported in ClinVar
• 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 5 ACMG points.

• PM1: In a domain RMT2 (size 223) in uniprot entity GAMT_HUMAN there are 36 pathogenic changes around while only 7 benign (84%) in NM_000156.6
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GAMT	NM_000156.6	c.182G>T	p.Gly61Val	missense_variant, splice_region_variant	Exon 2 of 6	ENST00000252288.8	NP_000147.1
GAMT	NM_138924.3	c.182G>T	p.Gly61Val	missense_variant, splice_region_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.182G>T	p.Gly61Val	missense_variant, splice_region_variant	Exon 2 of 6	1	NM_000156.6	ENSP00000252288.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.88e-7 AC: 1 AN: 1453432 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 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: 0.00

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

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.76
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Pathogenic	33
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.88	D;.;.
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	D;T;D
M_CAP	Pathogenic	0.63	D
MetaRNN	Pathogenic	0.88	D;D;D
MetaSVM	Pathogenic	0.91	D
MutationAssessor	Pathogenic	3.6	H;.;H
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-8.0	D;.;D
REVEL	Pathogenic	0.78
Sift	Uncertain	0.0010	D;.;D
Sift4G	Pathogenic	0.0	D;.;D
Polyphen		0.99	D;.;.
Vest4		0.81
MutPred		0.64		Loss of disorder (P = 0.0259);.;Loss of disorder (P = 0.0259);
MVP		0.96
MPC		0.23
ClinPred		1.0	D
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.94
gMVP		0.73

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.95
SpliceAI score (max)		0.070		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-1399937;