19-1399903-T-G

Position:

• chr19-1399903-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_000156.6(GAMT):​c.217A>C​(p.Ile73Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000131 in 152,172 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.000013 (0 hom., cov: 32)
• Consequence: GAMT NM_000156.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.92

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 4 ACMG points.

• PM1: In a helix (size 5) in uniprot entity GAMT_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_000156.6
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GAMT	NM_000156.6	c.217A>C	p.Ile73Leu	missense_variant	2/6	ENST00000252288.8	NP_000147.1
GAMT	NM_138924.3	c.217A>C	p.Ile73Leu	missense_variant	2/5		NP_620279.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GAMT	ENST00000252288.8	c.217A>C	p.Ile73Leu	missense_variant	2/6	1	NM_000156.6	ENSP00000252288.1
GAMT	ENST00000447102.8	c.217A>C	p.Ile73Leu	missense_variant	2/5	2		ENSP00000403536.2
GAMT	ENST00000640762.1	c.148A>C	p.Ile50Leu	missense_variant	2/6	5		ENSP00000492031.1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152172 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 33

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152172 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74346

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Benign	0.35	T;.;.
Eigen	Uncertain	0.21
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.88	D;D;D
M_CAP	Pathogenic	0.35	D
MetaRNN	Uncertain	0.66	D;D;D
MetaSVM	Uncertain	0.43	D
MutationAssessor	Uncertain	2.2	M;.;M
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.84	N;.;N
REVEL	Pathogenic	0.67
Sift	Benign	0.27	T;.;T
Sift4G	Benign	0.58	T;.;T
Polyphen		0.41	B;.;.
Vest4		0.86
MutPred		0.55		Loss of ubiquitination at K77 (P = 0.1453);.;Loss of ubiquitination at K77 (P = 0.1453);
MVP		0.72
MPC		0.22
ClinPred		0.90	D
GERP RS		4.3
Varity_R		0.37
gMVP		0.67

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs771107085; hg19: chr19-1399902;