19-1397213-T-G

Variant names:

• chr19-1397213-T-G
• rs659455
• NM_000156.6:c.*146A>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.*146A>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 0.0246 in 943,388 control chromosomes in the GnomAD database, including 1,640 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.070 (993 hom., cov: 33)
  • Exomes 𝑓: 0.016 (647 hom.)
• Consequence: GAMT NM_000156.6 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -2.87
• Publications: 2 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=-0.89).
• BP6: Variant 19-1397213-T-G is Benign according to our data. Variant chr19-1397213-T-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 328346.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.213 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.*146A>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.*146A>C		3_prime_UTR	Exon 6 of 6	ENSP00000252288.1	Q14353-1
	GAMT	ENST00000902474.1		c.*146A>C		3_prime_UTR	Exon 6 of 6	ENSP00000572533.1
	GAMT	ENST00000902472.1		c.*146A>C		3_prime_UTR	Exon 6 of 6	ENSP00000572531.1

Frequencies

GnomAD3 genomes AF: 0.0695 AC: 10548 AN: 151710 Hom.: 994 Cov.: 33

Gnomad AFR AF: 0.217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0423

Gnomad ASJ AF: 0.0291

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0188

Gnomad FIN AF: 0.00132

Gnomad MID AF: 0.0669

Gnomad NFE AF: 0.00904

Gnomad OTH AF: 0.0584

GnomAD4 exome AF: 0.0159 AC: 12625 AN: 791564 Hom.: 647 Cov.: 11 AF XY: 0.0153 AC XY: 6159 AN XY: 402176

African (AFR) AF: 0.218 AC: 4372 AN: 20012

American (AMR) AF: 0.0268 AC: 835 AN: 31130

Ashkenazi Jewish (ASJ) AF: 0.0265 AC: 474 AN: 17856

East Asian (EAS) AF: 0.0000611 AC: 2 AN: 32748

South Asian (SAS) AF: 0.0159 AC: 930 AN: 58334

European-Finnish (FIN) AF: 0.00233 AC: 72 AN: 30888

Middle Eastern (MID) AF: 0.0554 AC: 157 AN: 2832

European-Non Finnish (NFE) AF: 0.00844 AC: 4725 AN: 560044

Other (OTH) AF: 0.0280 AC: 1058 AN: 37720

GnomAD4 genome AF: 0.0696 AC: 10564 AN: 151824 Hom.: 993 Cov.: 33 AF XY: 0.0672 AC XY: 4986 AN XY: 74212

African (AFR) AF: 0.217 AC: 8957 AN: 41350

American (AMR) AF: 0.0423 AC: 645 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.0291 AC: 101 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5160

South Asian (SAS) AF: 0.0190 AC: 91 AN: 4792

European-Finnish (FIN) AF: 0.00132 AC: 14 AN: 10592

Middle Eastern (MID) AF: 0.0719 AC: 21 AN: 292

European-Non Finnish (NFE) AF: 0.00903 AC: 613 AN: 67886

Other (OTH) AF: 0.0578 AC: 122 AN: 2112

Alfa AF: 0.0363 Hom.: 87

Bravo AF: 0.0802

Asia WGS AF: 0.0250 AC: 85 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	-0.89
CADD	Benign	1.6
DANN	Benign	0.41
PhyloP100		-2.9
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: rs659455; hg19: chr19-1397212;