15-45361509-T-C

Variant names:

• chr15-45361509-T-C
• rs1049503
• NM_001482.3:c.*600A>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.*600A>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, in a continental population with >2000 alleles, is 0.2934 (2554/8704 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: 316206). 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/CA10647042/MONDO:0012996/025

• Frequency:
  • Genomes: 𝑓 0.32 (8903 hom., cov: 32)
  • Exomes 𝑓: 0.30 (126 hom.)
• Consequence: GATM NM_001482.3 3_prime_UTR
• Clinical Significance: Benign reviewed by expert panel B:3
• Conservation: PhyloP100: 1.85
• Publications: 14 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.*600A>G		3_prime_UTR	Exon 9 of 9	NP_001473.1	P50440-1
	GATM	NM_001321015.2		c.*600A>G		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.*600A>G		3_prime_UTR	Exon 9 of 9	ENSP00000379895.3	P50440-1
	GATM	ENST00000558362.5	TSL:1	n.3528A>G		non_coding_transcript_exon	Exon 8 of 8
	GATM	ENST00000887717.1		c.*600A>G		3_prime_UTR	Exon 9 of 9	ENSP00000557776.1

Frequencies

GnomAD3 genomes AF: 0.320 AC: 48623 AN: 151944 Hom.: 8881 Cov.: 32

Gnomad AFR AF: 0.297

Gnomad AMI AF: 0.179

Gnomad AMR AF: 0.473

Gnomad ASJ AF: 0.348

Gnomad EAS AF: 0.831

Gnomad SAS AF: 0.353

Gnomad FIN AF: 0.309

Gnomad MID AF: 0.269

Gnomad NFE AF: 0.260

Gnomad OTH AF: 0.342

GnomAD4 exome AF: 0.295 AC: 678 AN: 2298 Hom.: 126 Cov.: 0 AF XY: 0.307 AC XY: 362 AN XY: 1178

African (AFR) AF: 0.324 AC: 33 AN: 102

American (AMR) AF: 0.543 AC: 38 AN: 70

Ashkenazi Jewish (ASJ) AF: 0.375 AC: 45 AN: 120

East Asian (EAS) AF: 0.875 AC: 84 AN: 96

South Asian (SAS) AF: 0.423 AC: 11 AN: 26

European-Finnish (FIN) AF: 0.350 AC: 21 AN: 60

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2

European-Non Finnish (NFE) AF: 0.238 AC: 399 AN: 1678

Other (OTH) AF: 0.326 AC: 47 AN: 144

GnomAD4 genome AF: 0.320 AC: 48670 AN: 152062 Hom.: 8903 Cov.: 32 AF XY: 0.329 AC XY: 24439 AN XY: 74324

African (AFR) AF: 0.297 AC: 12316 AN: 41464

American (AMR) AF: 0.474 AC: 7244 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.348 AC: 1209 AN: 3470

East Asian (EAS) AF: 0.832 AC: 4318 AN: 5190

South Asian (SAS) AF: 0.351 AC: 1694 AN: 4822

European-Finnish (FIN) AF: 0.309 AC: 3267 AN: 10566

Middle Eastern (MID) AF: 0.279 AC: 82 AN: 294

European-Non Finnish (NFE) AF: 0.260 AC: 17648 AN: 67954

Other (OTH) AF: 0.345 AC: 729 AN: 2112

Alfa AF: 0.248 Hom.: 1738

Bravo AF: 0.338

Asia WGS AF: 0.560 AC: 1929 AN: 3454

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	-0.44
CADD	Benign	15
DANN	Benign	0.87
PhyloP100		1.9
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: rs1049503; hg19: chr15-45653707;