chr19-1397348-G-A

Position:

• chr19-1397348-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BA1 BP4 BP7 BS2

This summary comes from the ClinGen Evidence Repository: The NM_000156.6:c.*11C>T variant is a nucleotide substitution in the 3'UTR of GAMT. Because the variant is located in the 3'UTR, it is not expected to alter the amino acid sequence of the gene product. The highest population minor allele frequency in gnomAD v2.1.1 is 0.05828 (1381/23694 alleles) in the African / African-American population, which is higher than the ClinGen CCDS VCEP’s threshold for BA1 (>0.003), and therefore meets this criterion (BA1). Furthermore, the variant has been observed in the homozygous state in 37 individuals out of 134,627 in gnomAD v2.1.1. Given the severity and early onset of the symptoms of GAMT deficiency, this data suggests that the variant does not cause this condition (BS2). It is not predicted to not impact splicing by Splice AI and VarSeak, and the nucleotide is not highly conserved (BP4, BP7). This variant is noted in ClinVar (ID 204598). In summary, this variant meets the criteria to be classified as benign for GAMT deficiency. GAMT-specific ACMG/AMP codes met, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes VCEP (Specifications Version 1.1.0): BA1, BS2, BP4, BP7.(Classification approved by the ClinGen CCDS VCEP on June 6, 2022). LINK:https://erepo.genome.network/evrepo/ui/classification/CA291022/MONDO:0012999/026

• Frequency:
  • Genomes: 𝑓 0.017 (82 hom., cov: 33)
  • Exomes 𝑓: 0.0016 (57 hom.)
• Consequence: GAMT ENST00000252288 3_prime_UTR
• Clinical Significance: Benign reviewed by expert panel B:4
• Conservation: PhyloP100: -0.00700

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 Benign. Variant got -14 ACMG points.

• BP4: For more information check the summary or visit ClinGen Evidence Repository.
• BP7: For more information check the summary or visit ClinGen Evidence Repository.
• BS2: For more information check the summary or visit ClinGen Evidence Repository.
• BA1: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GAMT	NM_000156.6	c.*11C>T		3_prime_UTR_variant	6/6	ENST00000252288.8	NP_000147.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GAMT	ENST00000252288	c.*11C>T		3_prime_UTR_variant	6/6	1	NM_000156.6	ENSP00000252288.1
GAMT	ENST00000640762	c.*11C>T		3_prime_UTR_variant	6/6	5		ENSP00000492031.1
GAMT	ENST00000640164.1	n.*35C>T		downstream_gene_variant		2

Frequencies

GnomAD3 genomes AF: 0.0174 AC: 2651 AN: 152226 Hom.: 82 Cov.: 33

Gnomad AFR AF: 0.0592

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00987

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.0143

GnomAD3 exomes AF: 0.00440 AC: 1046 AN: 237884 Hom.: 25 AF XY: 0.00320 AC XY: 415 AN XY: 129596

Gnomad AFR exome AF: 0.0603

Gnomad AMR exome AF: 0.00356

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000333

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000932

Gnomad OTH exome AF: 0.00171

GnomAD4 exome AF: 0.00163 AC: 2372 AN: 1455408 Hom.: 57 Cov.: 30 AF XY: 0.00140 AC XY: 1011 AN XY: 723898

Gnomad4 AFR exome AF: 0.0555

Gnomad4 AMR exome AF: 0.00430

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000117

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000540

Gnomad4 OTH exome AF: 0.00406

GnomAD4 genome AF: 0.0174 AC: 2649 AN: 152344 Hom.: 82 Cov.: 33 AF XY: 0.0167 AC XY: 1247 AN XY: 74490

Gnomad4 AFR AF: 0.0590

Gnomad4 AMR AF: 0.00986

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000191

Gnomad4 OTH AF: 0.0142

Alfa AF: 0.00873 Hom.: 7

Bravo AF: 0.0191

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: reviewed by expert panel

Submissions by phenotype

Deficiency of guanidinoacetate methyltransferase Benign:2

Benign, reviewed by expert panel	curation	ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel, ClinGen	Jun 06, 2022	The NM_000156.6:c.*11C>T variant is a nucleotide substitution in the 3'UTR of GAMT. Because the variant is located in the 3'UTR, it is not expected to alter the amino acid sequence of the gene product. The highest population minor allele frequency in gnomAD v2.1.1 is 0.05828 (1381/23694 alleles) in the African / African-American population, which is higher than the ClinGen CCDS VCEP’s threshold for BA1 (>0.003), and therefore meets this criterion (BA1). Furthermore, the variant has been observed in the homozygous state in 37 individuals out of 134,627 in gnomAD v2.1.1. Given the severity and early onset of the symptoms of GAMT deficiency, this data suggests that the variant does not cause this condition (BS2). It is not predicted to not impact splicing by Splice AI and VarSeak, and the nucleotide is not highly conserved (BP4, BP7). This variant is noted in ClinVar (ID 204598). In summary, this variant meets the criteria to be classified as benign for GAMT deficiency. GAMT-specific ACMG/AMP codes met, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes VCEP (Specifications Version 1.1.0): BA1, BS2, BP4, BP7. (Classification approved by the ClinGen CCDS VCEP on June 6, 2022). -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 10, 2012

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.040
DANN	Benign	0.59
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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

Publications

LitVar

Other links and lift over

dbSNP: rs149268921; hg19: chr19-1397347;