NM_001482.3:c.*734_*735insCA

Variant names:

• chr15-45361374-C-CTG
• rs35410548
• NM_001482.3:c.*734_*735insCA

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.*734_*735insCA variant inserts two nucleotides 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 0.8397 (7277/8666 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: 316203). 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/CA10636071/MONDO:0012996/025

• Frequency:
  • Genomes: 𝑓 0.56 (27212 hom., cov: 0)
  • Exomes 𝑓: 0.67 (1 hom.)
• Consequence: GATM NM_001482.3 3_prime_UTR
• Clinical Significance: Benign reviewed by expert panel B:2
• Conservation: PhyloP100: 2.32
• Publications: 4 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.*734_*735insCA		3_prime_UTR	Exon 9 of 9	NP_001473.1	P50440-1
	GATM	NM_001321015.2		c.*734_*735insCA		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.*734_*735insCA		3_prime_UTR	Exon 9 of 9	ENSP00000379895.3	P50440-1
	GATM	ENST00000558362.5	TSL:1	n.3662_3663insCA		non_coding_transcript_exon	Exon 8 of 8
	GATM	ENST00000887717.1		c.*734_*735insCA		3_prime_UTR	Exon 9 of 9	ENSP00000557776.1

Frequencies

GnomAD3 genomes AF: 0.559 AC: 84775 AN: 151520 Hom.: 27157 Cov.: 0

Gnomad AFR AF: 0.840

Gnomad AMI AF: 0.233

Gnomad AMR AF: 0.619

Gnomad ASJ AF: 0.534

Gnomad EAS AF: 0.908

Gnomad SAS AF: 0.595

Gnomad FIN AF: 0.408

Gnomad MID AF: 0.552

Gnomad NFE AF: 0.376

Gnomad OTH AF: 0.558

GnomAD4 exome AF: 0.667 AC: 4 AN: 6 Hom.: 1 Cov.: 0 AF XY: 0.500 AC XY: 1 AN XY: 2

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

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) AF: 0.667 AC: 4 AN: 6

Other (OTH) AC: 0 AN: 0

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000000770867), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.560 AC: 84893 AN: 151636 Hom.: 27212 Cov.: 0 AF XY: 0.566 AC XY: 41959 AN XY: 74068

African (AFR) AF: 0.840 AC: 34750 AN: 41350

American (AMR) AF: 0.619 AC: 9419 AN: 15210

Ashkenazi Jewish (ASJ) AF: 0.534 AC: 1847 AN: 3462

East Asian (EAS) AF: 0.908 AC: 4695 AN: 5168

South Asian (SAS) AF: 0.594 AC: 2855 AN: 4808

European-Finnish (FIN) AF: 0.408 AC: 4276 AN: 10478

Middle Eastern (MID) AF: 0.559 AC: 161 AN: 288

European-Non Finnish (NFE) AF: 0.376 AC: 25494 AN: 67856

Other (OTH) AF: 0.562 AC: 1184 AN: 2108

Alfa AF: 0.300 Hom.: 721

Bravo AF: 0.592

Asia WGS AF: 0.738 AC: 2545 AN: 3454

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	2	Arginine:glycine amidinotransferase deficiency (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.3
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs35410548; hg19: chr15-45653572; COSMIC: COSV67540087; COSMIC: COSV67540087;