19-1399841-G-C

Position:

• chr19-1399841-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The ENST00000252288.8(GAMT):​c.279C>G​(p.Asp93Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 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. D93V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GAMT ENST00000252288.8 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.20

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 2 ACMG points.

• PM1: In a domain RMT2 (size 223) in uniprot entity GAMT_HUMAN there are 70 pathogenic changes around while only 17 benign (80%) in ENST00000252288.8
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12100986).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GAMT	NM_000156.6	c.279C>G	p.Asp93Glu	missense_variant	2/6	ENST00000252288.8	NP_000147.1
GAMT	NM_138924.3	c.279C>G	p.Asp93Glu	missense_variant	2/5		NP_620279.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GAMT	ENST00000252288.8	c.279C>G	p.Asp93Glu	missense_variant	2/6	1	NM_000156.6	ENSP00000252288	P1
GAMT	ENST00000447102.8	c.279C>G	p.Asp93Glu	missense_variant	2/5	2		ENSP00000403536
GAMT	ENST00000640762.1	c.210C>G	p.Asp70Glu	missense_variant	2/6	5		ENSP00000492031
GAMT	ENST00000591788.3			upstream_gene_variant		5		ENSP00000466341

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.089	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	0.011
DANN	Benign	0.93
DEOGEN2	Benign	0.34	T;.;.
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.094	N
LIST_S2	Benign	0.74	T;T;T
M_CAP	Uncertain	0.086	D
MetaRNN	Benign	0.12	T;T;T
MetaSVM	Benign	-0.87	T
MutationAssessor	Uncertain	2.1	M;.;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.2	N;.;N
REVEL	Benign	0.25
Sift	Benign	0.48	T;.;T
Sift4G	Benign	0.40	T;.;T
Polyphen		0.0010	B;.;.
Vest4		0.28
MutPred		0.48		Gain of MoRF binding (P = 0.2313);.;Gain of MoRF binding (P = 0.2313);
MVP		0.61
MPC		0.14
ClinPred		0.20	T
GERP RS		-7.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.14
gMVP		0.41

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs144630886; hg19: chr19-1399840;