rs148838075

Variant names:

• chr19-1399806-C-A
• rs148838075
• NM_000156.6:c.314G>T

Your query was ambiguous. Multiple possible variants found:

• chr19-1399806-C-A
• chr19-1399806-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000156.6(GAMT):​c.314G>T​(p.Arg105Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000212 in 1,417,888 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 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. R105Q) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: GAMT NM_000156.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.51
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21358547).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GAMT	NM_000156.6	c.314G>T	p.Arg105Leu	missense_variant	Exon 2 of 6	ENST00000252288.8	NP_000147.1
GAMT	NM_138924.3	c.314G>T	p.Arg105Leu	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.314G>T	p.Arg105Leu	missense_variant	Exon 2 of 6	1	NM_000156.6	ENSP00000252288.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000212 AC: 3 AN: 1417888 Hom.: 0 Cov.: 33 AF XY: 0.00000285 AC XY: 2 AN XY: 701714

African (AFR) AF: 0.00 AC: 0 AN: 32462

American (AMR) AF: 0.00 AC: 0 AN: 38672

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25332

East Asian (EAS) AF: 0.00 AC: 0 AN: 37228

South Asian (SAS) AF: 0.00 AC: 0 AN: 81052

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48172

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5718

European-Non Finnish (NFE) AF: 0.00000275 AC: 3 AN: 1090538

Other (OTH) AF: 0.00 AC: 0 AN: 58714

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.093	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	0.031
DANN	Benign	0.93
DEOGEN2	Uncertain	0.61	D;.;.
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.033	N
LIST_S2	Benign	0.78	T;T;T
M_CAP	Uncertain	0.23	D
MetaRNN	Benign	0.21	T;T;T
MetaSVM	Benign	-0.60	T
MutationAssessor	Benign	1.5	L;.;L
PhyloP100		-3.5
PrimateAI	Benign	0.23	T
PROVEAN	Uncertain	-2.7	D;.;D
REVEL	Benign	0.19
Sift	Benign	0.20	T;.;T
Sift4G	Benign	0.27	T;.;T
Polyphen		0.0030	B;.;.
Vest4		0.33
MutPred		0.43		Loss of MoRF binding (P = 0.0085);.;Loss of MoRF binding (P = 0.0085);
MVP		0.64
MPC		0.18
ClinPred		0.095	T
GERP RS		-6.5
PromoterAI		0.00060	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.25
gMVP		0.46
Mutation Taster		=83/17	polymorphism

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

Other links and lift over

dbSNP: rs148838075; hg19: chr19-1399805; COSMIC: COSV108027878; COSMIC: COSV108027878;