19-1399548-T-G

Variant names:

• chr19-1399548-T-G
• rs771827261
• NM_000156.6:c.367A>C

Variant summary

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

The NM_138924.3(GAMT):​c.367A>C​(p.Thr123Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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)
• Consequence: GAMT NM_138924.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.92
• Publications: 1 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_138924.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GAMT	NM_000156.6	MANE Select	c.367A>C	p.Thr123Pro	missense	Exon 3 of 6	NP_000147.1
	GAMT	NM_138924.3		c.367A>C	p.Thr123Pro	missense	Exon 3 of 5	NP_620279.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GAMT	ENST00000252288.8	TSL:1 MANE Select	c.367A>C	p.Thr123Pro	missense	Exon 3 of 6	ENSP00000252288.1
	GAMT	ENST00000902474.1		c.637A>C	p.Thr213Pro	missense	Exon 3 of 6	ENSP00000572533.1
	GAMT	ENST00000447102.8	TSL:2	c.367A>C	p.Thr123Pro	missense	Exon 3 of 5	ENSP00000403536.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.64	D
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.65	T
M_CAP	Uncertain	0.26	D
MetaRNN	Uncertain	0.58	D
MetaSVM	Uncertain	0.0094	D
MutationAssessor	Uncertain	2.2	M
PhyloP100		4.9
PrimateAI	Benign	0.43	T
PROVEAN	Uncertain	-2.6	D
REVEL	Uncertain	0.62
Sift	Benign	0.18	T
Sift4G	Benign	0.095	T
Polyphen		0.95	P
Vest4		0.41
MutPred		0.30		Gain of catalytic residue at T123 (P = 0.0525)
MVP		0.89
MPC		0.35
ClinPred		0.96	D
GERP RS		3.8
PromoterAI		-0.0092	Neutral
Varity_R		0.91
gMVP		0.84
Mutation Taster		=20/80	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs771827261; hg19: chr19-1399547;