rs77168423

Variant names:

• chr19-1399938-C-A
• rs77168423
• 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 Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM2 PM5 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G61E) has been classified as Benign.

• 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
• Publications: 0 publications found

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]

GAMT Gene-Disease associations (from GenCC):

• guanidinoacetate methyltransferase deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain 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 chr19-1401296-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 predictors support a deleterious 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

African (AFR) AF: 0.00 AC: 0 AN: 33408

American (AMR) AF: 0.00 AC: 0 AN: 43886

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25920

East Asian (EAS) AF: 0.00 AC: 0 AN: 39446

South Asian (SAS) AF: 0.00 AC: 0 AN: 84892

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 9.01e-7 AC: 1 AN: 1109394

Other (OTH) AF: 0.00 AC: 0 AN: 60100

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
PhyloP100		7.6
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
PromoterAI		0.041	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.94
gMVP		0.73
Mutation Taster		=23/77	disease causing

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

Other links and lift over

dbSNP: rs77168423; hg19: chr19-1399937;