chr19-1397348-G-A

Variant names:

• chr19-1397348-G-A
• rs149268921
• NM_000156.6:c.*11C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP7 BS2 BA1 BP4

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 NM_000156.6 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]

ACMG classification

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
GAMT	NM_000156.6	c.*11C>T		3_prime_UTR_variant	Exon 6 of 6	ENST00000252288.8	NP_000147.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GAMT	ENST00000252288	c.*11C>T		3_prime_UTR_variant	Exon 6 of 6	1	NM_000156.6	ENSP00000252288.1
GAMT	ENST00000640762	c.*11C>T		3_prime_UTR_variant	Exon 6 of 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

GnomAD2 exomes AF: 0.00440 AC: 1046 AN: 237884 AF XY: 0.00320

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 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 AC: 1853 AN: 33414

Gnomad4 AMR exome AF: 0.00430 AC: 190 AN: 44210

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 26012

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39444

Gnomad4 SAS exome AF: 0.000117 AC: 10 AN: 85800

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 50282

Gnomad4 NFE exome AF: 0.0000540 AC: 60 AN: 1110344

Gnomad4 Remaining exome AF: 0.00406 AC: 244 AN: 60144

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 AC: 0.0590188 AN: 0.0590188

Gnomad4 AMR AF: 0.00986 AC: 0.00986155 AN: 0.00986155

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.000191 AC: 0.000191115 AN: 0.000191115

Gnomad4 OTH AF: 0.0142 AC: 0.0141911 AN: 0.0141911

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

Jun 06, 2022

ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel, ClinGen

Significance: Benign

Review Status: reviewed by expert panel

Collection Method: curation

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). -

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

May 10, 2012

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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
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

Publications

LitVar

Other links and lift over

dbSNP: rs149268921; hg19: chr19-1397347;