rs1049518

Variant names:

• chr15-45361169-G-A
• rs1049518
• NM_001482.3:c.*940C>T

Your query was ambiguous. Multiple possible variants found:

• chr15-45361169-G-A
• chr15-45361169-G-C
• chr15-45361169-G-T

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.*940C>T 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, in a population with >2000 alleles, is 0.8433 (7330/8692 alleles) in the African 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: 316200, 1 star review status) with one submitter classifying the variant as benign. 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 1.0, ; classification approved June 6, 2022): BA1. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10647041/MONDO:0012996/025

• Frequency:
  • Genomes: 𝑓 0.56 (27429 hom., cov: 32)
  • Failed GnomAD Quality Control
• Consequence: GATM NM_001482.3 3_prime_UTR
• Clinical Significance: Benign reviewed by expert panel B:3
• Conservation: PhyloP100: 2.40
• Publications: 20 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: Orphanet, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), ClinGen
• 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001482.3. 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
	GATM	NM_001482.3	MANE Select	c.*940C>T		3_prime_UTR	Exon 9 of 9	NP_001473.1	P50440-1
	GATM	NM_001321015.2		c.*940C>T		3_prime_UTR	Exon 12 of 12	NP_001307944.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GATM	ENST00000396659.8	TSL:1 MANE Select	c.*940C>T		3_prime_UTR	Exon 9 of 9	ENSP00000379895.3	P50440-1
	GATM	ENST00000558362.5	TSL:1	n.3868C>T		non_coding_transcript_exon	Exon 8 of 8
	GATM	ENST00000887717.1		c.*940C>T		3_prime_UTR	Exon 9 of 9	ENSP00000557776.1

Frequencies

GnomAD3 genomes AF: 0.562 AC: 85195 AN: 151724 Hom.: 27374 Cov.: 32

Gnomad AFR AF: 0.843

Gnomad AMI AF: 0.235

Gnomad AMR AF: 0.621

Gnomad ASJ AF: 0.534

Gnomad EAS AF: 0.909

Gnomad SAS AF: 0.595

Gnomad FIN AF: 0.412

Gnomad MID AF: 0.551

Gnomad NFE AF: 0.377

Gnomad OTH AF: 0.558

GnomAD4 exome Data not reliable, filtered out with message: AC0 AC: 0 AN: 0 Hom.: 0 Cov.: 0 AC XY: 0 AN XY: 0

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AC: 0 AN: 0

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.562 AC: 85313 AN: 151842 Hom.: 27429 Cov.: 32 AF XY: 0.569 AC XY: 42192 AN XY: 74174

African (AFR) AF: 0.843 AC: 34991 AN: 41520

American (AMR) AF: 0.621 AC: 9481 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.534 AC: 1851 AN: 3466

East Asian (EAS) AF: 0.909 AC: 4711 AN: 5184

South Asian (SAS) AF: 0.593 AC: 2855 AN: 4812

European-Finnish (FIN) AF: 0.412 AC: 4310 AN: 10464

Middle Eastern (MID) AF: 0.558 AC: 164 AN: 294

European-Non Finnish (NFE) AF: 0.377 AC: 25551 AN: 67830

Other (OTH) AF: 0.563 AC: 1186 AN: 2108

Alfa AF: 0.439 Hom.: 31336

Bravo AF: 0.592

Asia WGS AF: 0.736 AC: 2546 AN: 3464

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	2	Arginine:glycine amidinotransferase deficiency (2)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	6.7
DANN	Benign	0.69
PhyloP100		2.4
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: rs1049518; hg19: chr15-45653367;