19-1397083-G-A

Variant names:

• chr19-1397083-G-A
• rs266810
• NM_000156.6:c.*276C>T

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.*276C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0356 in 469,006 control chromosomes in the GnomAD database, including 1,329 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 (1009 hom., cov: 33)
  • Exomes 𝑓: 0.019 (320 hom.)
• Consequence: GAMT NM_000156.6 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.354
• 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=-0.92).
• BP6: Variant 19-1397083-G-A is Benign according to our data. Variant chr19-1397083-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 328344.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.*276C>T		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.*276C>T		3_prime_UTR	Exon 6 of 6	ENSP00000252288.1	Q14353-1
	GAMT	ENST00000902474.1		c.*276C>T		downstream_gene	N/A	ENSP00000572533.1
	GAMT	ENST00000902472.1		c.*276C>T		downstream_gene	N/A	ENSP00000572531.1

Frequencies

GnomAD3 genomes AF: 0.0695 AC: 10578 AN: 152114 Hom.: 1010 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: 0.0180

Gnomad FIN AF: 0.00132

Gnomad MID AF: 0.0665

Gnomad NFE AF: 0.00903

Gnomad OTH AF: 0.0584

GnomAD4 exome AF: 0.0193 AC: 6117 AN: 316776 Hom.: 320 Cov.: 3 AF XY: 0.0185 AC XY: 3050 AN XY: 164750

African (AFR) AF: 0.225 AC: 2211 AN: 9830

American (AMR) AF: 0.0336 AC: 492 AN: 14624

Ashkenazi Jewish (ASJ) AF: 0.0278 AC: 279 AN: 10054

East Asian (EAS) AF: 0.0000915 AC: 2 AN: 21858

South Asian (SAS) AF: 0.0173 AC: 555 AN: 32140

European-Finnish (FIN) AF: 0.00237 AC: 47 AN: 19812

Middle Eastern (MID) AF: 0.0556 AC: 78 AN: 1404

European-Non Finnish (NFE) AF: 0.0100 AC: 1883 AN: 188380

Other (OTH) AF: 0.0305 AC: 570 AN: 18674

GnomAD4 genome AF: 0.0696 AC: 10596 AN: 152230 Hom.: 1009 Cov.: 33 AF XY: 0.0672 AC XY: 5001 AN XY: 74438

African (AFR) AF: 0.217 AC: 8990 AN: 41516

American (AMR) AF: 0.0423 AC: 647 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0291 AC: 101 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.0182 AC: 88 AN: 4822

European-Finnish (FIN) AF: 0.00132 AC: 14 AN: 10616

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

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

Other (OTH) AF: 0.0578 AC: 122 AN: 2110

Alfa AF: 0.0755 Hom.: 196

Bravo AF: 0.0802

Asia WGS AF: 0.0250 AC: 87 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	-0.92
CADD	Benign	1.6
DANN	Benign	0.59
PhyloP100		-0.35
Mutation Taster		=92/8	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs266810; hg19: chr19-1397082;