19-1397444-G-T

Position:

• chr19-1397444-G-T

Variant summary

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

The NM_000156.6(GAMT):​c.626C>A​(p.Thr209Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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. T209M) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: GAMT NM_000156.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.84

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a domain RMT2 (size 223) in uniprot entity GAMT_HUMAN there are 36 pathogenic changes around while only 7 benign (84%) 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.626C>A	p.Thr209Lys	missense_variant	6/6	ENST00000252288.8	NP_000147.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GAMT	ENST00000252288.8	c.626C>A	p.Thr209Lys	missense_variant	6/6	1	NM_000156.6	ENSP00000252288.1
GAMT	ENST00000640762.1	c.557C>A	p.Thr186Lys	missense_variant	6/6	5		ENSP00000492031.1
GAMT	ENST00000640164.1	n.459C>A		non_coding_transcript_exon_variant	4/4	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1458218 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 725492

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Benign	14
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.65	D;.
Eigen	Benign	0.16
Eigen_PC	Benign	0.071
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.68	T;T
M_CAP	Benign	0.079	D
MetaRNN	Uncertain	0.72	D;D
MetaSVM	Uncertain	0.31	D
MutationAssessor	Pathogenic	3.1	M;.
PROVEAN	Uncertain	-2.6	D;.
REVEL	Uncertain	0.56
Sift	Benign	0.17	T;.
Sift4G	Benign	0.085	T;.
Polyphen		0.99	D;.
Vest4		0.49
MutPred		0.38		Gain of ubiquitination at T209 (P = 0.0155);.;
MVP		0.91
ClinPred		0.85	D
GERP RS		5.1
Varity_R		0.53

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

Publications

LitVar

Other links and lift over

dbSNP: rs17851582; hg19: chr19-1397443;