NM_000156.6:c.*151T>C

Variant names:

• chr19-1397208-A-G
• rs659460
• NM_000156.6:c.*151T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000156.6(GAMT):​c.*151T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0254 in 871,618 control chromosomes in the GnomAD database, including 1,574 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.069 (982 hom., cov: 33)
  • Exomes 𝑓: 0.016 (592 hom.)
• Consequence: GAMT NM_000156.6 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.292
• Publications: 3 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: Ambry Genetics, Orphanet, G2P, ClinGen, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 19-1397208-A-G is Benign according to our data. Variant chr19-1397208-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 328345.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.212 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000156.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GAMT	NM_000156.6	MANE Select	c.*151T>C		3_prime_UTR	Exon 6 of 6	NP_000147.1	Q14353-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GAMT	ENST00000252288.8	TSL:1 MANE Select	c.*151T>C		3_prime_UTR	Exon 6 of 6	ENSP00000252288.1	Q14353-1
	GAMT	ENST00000902474.1		c.*151T>C		3_prime_UTR	Exon 6 of 6	ENSP00000572533.1
	GAMT	ENST00000902472.1		c.*151T>C		3_prime_UTR	Exon 6 of 6	ENSP00000572531.1

Frequencies

GnomAD3 genomes AF: 0.0692 AC: 10524 AN: 152072 Hom.: 983 Cov.: 33

Gnomad AFR AF: 0.216

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0423

Gnomad ASJ AF: 0.0291

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0186

Gnomad FIN AF: 0.00132

Gnomad MID AF: 0.0665

Gnomad NFE AF: 0.00903

Gnomad OTH AF: 0.0588

GnomAD4 exome AF: 0.0161 AC: 11616 AN: 719432 Hom.: 592 Cov.: 9 AF XY: 0.0155 AC XY: 5675 AN XY: 366478

African (AFR) AF: 0.220 AC: 4008 AN: 18256

American (AMR) AF: 0.0296 AC: 805 AN: 27226

Ashkenazi Jewish (ASJ) AF: 0.0272 AC: 453 AN: 16650

East Asian (EAS) AF: 0.0000619 AC: 2 AN: 32310

South Asian (SAS) AF: 0.0159 AC: 882 AN: 55346

European-Finnish (FIN) AF: 0.00235 AC: 71 AN: 30260

Middle Eastern (MID) AF: 0.0571 AC: 150 AN: 2628

European-Non Finnish (NFE) AF: 0.00846 AC: 4243 AN: 501764

Other (OTH) AF: 0.0286 AC: 1002 AN: 34992

GnomAD4 genome AF: 0.0693 AC: 10541 AN: 152186 Hom.: 982 Cov.: 33 AF XY: 0.0669 AC XY: 4980 AN XY: 74424

African (AFR) AF: 0.215 AC: 8931 AN: 41454

American (AMR) AF: 0.0423 AC: 647 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0291 AC: 101 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.0188 AC: 91 AN: 4828

European-Finnish (FIN) AF: 0.00132 AC: 14 AN: 10624

Middle Eastern (MID) AF: 0.0714 AC: 21 AN: 294

European-Non Finnish (NFE) AF: 0.00901 AC: 613 AN: 68006

Other (OTH) AF: 0.0582 AC: 123 AN: 2114

Alfa AF: 0.0555 Hom.: 127

Bravo AF: 0.0801

Asia WGS AF: 0.0250 AC: 86 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Deficiency of guanidinoacetate methyltransferase (1)
-	-	1	Leigh syndrome (1)
-	-	1	Mitochondrial complex I deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	4.6
DANN	Benign	0.57
PhyloP100		-0.29
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs659460; hg19: chr19-1397207; COSMIC: COSV99282687; COSMIC: COSV99282687;