chr15-45362082-G-C

Variant names:

• chr15-45362082-G-C
• rs200143728
• ENST00000558362.5:n.2955C>G

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

This summary comes from the ClinGen Evidence Repository: The NM_001482.3:c.*27C>G variant is a single nucleotide substitution in the 3'UTR of GATM. Because the variant is located in the 3'UTR, it is not expected to alter the amino acid sequence. The highest population minor allele frequency in gnomAD v2.1.1 is 0.000856 (110/128560 alleles) in the non-Finnish European population, which is higher than the ClinGen CCDS VCEP’s threshold for BA1 (>0.0005), and therefore meets this criterion (BA1). There is a ClinVar entry for this variant (Variation ID: 316209). In summary, this variant meets the criteria to be classified as benign for AGAT deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 1.1.0): BA1.(Classification approved by the ClinGen CCDS VCEP on June 6, 2022). LINK:https://erepo.genome.network/evrepo/ui/classification/CA7542745/MONDO:0012996/025

• Frequency:
  • Genomes: 𝑓 0.00052 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00068 (0 hom.)
• Consequence: GATM NM_001482.3 3_prime_UTR
• Clinical Significance: Benign reviewed by expert panel U:1 B:1
• Conservation: PhyloP100: 1.57
• Publications: 1 publications found

Genes affected

GATM (HGNC:4175): (glycine amidinotransferase) This gene encodes a mitochondrial enzyme that belongs to the amidinotransferase family. This enzyme is involved in creatine biosynthesis, whereby it catalyzes the transfer of a guanido group from L-arginine to glycine, resulting in guanidinoacetic acid, the immediate precursor of creatine. Mutations in this gene cause arginine:glycine amidinotransferase deficiency, an inborn error of creatine synthesis characterized by cognitive disability, language impairment, and behavioral disorders. [provided by RefSeq, Jul 2008]

GATM Gene-Disease associations (from GenCC):

• AGAT deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Orphanet, Ambry Genetics, G2P
• Fanconi renotubular syndrome 1

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• primary Fanconi syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GATM	NM_001482.3	c.*27C>G		3_prime_UTR_variant	Exon 9 of 9	ENST00000396659.8	NP_001473.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GATM	ENST00000396659.8	c.*27C>G		3_prime_UTR_variant	Exon 9 of 9	1	NM_001482.3	ENSP00000379895.3

Frequencies

GnomAD3 genomes AF: 0.000519 AC: 79 AN: 152138 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000911

Gnomad OTH AF: 0.000955

GnomAD2 exomes AF: 0.000471 AC: 118 AN: 250420 AF XY: 0.000458

Gnomad AFR exome AF: 0.0000617

Gnomad AMR exome AF: 0.000319

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000419

Gnomad NFE exome AF: 0.000831

Gnomad OTH exome AF: 0.000492

GnomAD4 exome AF: 0.000680 AC: 851 AN: 1250650 Hom.: 0 Cov.: 18 AF XY: 0.000665 AC XY: 421 AN XY: 632728

African (AFR) AF: 0.000106 AC: 3 AN: 28314

American (AMR) AF: 0.000225 AC: 10 AN: 44418

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24776

East Asian (EAS) AF: 0.00 AC: 0 AN: 38452

South Asian (SAS) AF: 0.0000123 AC: 1 AN: 81624

European-Finnish (FIN) AF: 0.000771 AC: 41 AN: 53190

Middle Eastern (MID) AF: 0.000373 AC: 2 AN: 5358

European-Non Finnish (NFE) AF: 0.000840 AC: 774 AN: 921324

Other (OTH) AF: 0.000376 AC: 20 AN: 53194

GnomAD4 genome AF: 0.000519 AC: 79 AN: 152256 Hom.: 1 Cov.: 32 AF XY: 0.000484 AC XY: 36 AN XY: 74440

African (AFR) AF: 0.000144 AC: 6 AN: 41542

American (AMR) AF: 0.000196 AC: 3 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.000565 AC: 6 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000912 AC: 62 AN: 68012

Other (OTH) AF: 0.000945 AC: 2 AN: 2116

Alfa AF: 0.000717 Hom.: 0

Bravo AF: 0.000518

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:1

Revision: reviewed by expert panel

Submissions by phenotype

Arginine:glycine amidinotransferase deficiency Uncertain:1 Benign:1

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_001482.3:c.*27C>G variant is a single nucleotide substitution in the 3'UTR of GATM. Because the variant is located in the 3'UTR, it is not expected to alter the amino acid sequence. The highest population minor allele frequency in gnomAD v2.1.1 is 0.000856 (110/128560 alleles) in the non-Finnish European population, which is higher than the ClinGen CCDS VCEP’s threshold for BA1 (>0.0005), and therefore meets this criterion (BA1). There is a ClinVar entry for this variant (Variation ID: 316209). In summary, this variant meets the criteria to be classified as benign for AGAT deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 1.1.0): BA1. (Classification approved by the ClinGen CCDS VCEP on June 6, 2022). -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	11
DANN	Benign	0.72
PhyloP100		1.6
Mutation Taster		=100/0	polymorphism

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: rs200143728; hg19: chr15-45654280;