15-45361374-C-CTG

Variant names:

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

Scores

Not classified

Clinical Significance

Benign reviewed by expert panel B:2

Conservation

PhyloP100: 2.32

Publications

4 publications found

Variant links:

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

GATM links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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 link	c.734_735insCA		3_prime_UTR_variant	Exon 9 of 9	ENST00000396659.8	NP_001473.1	P50440-1A0A140VK19

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GATM	ENST00000396659.8 link	c.734_735insCA		3_prime_UTR_variant	Exon 9 of 9	1	NM_001482.3	ENSP00000379895.3		P50440-1

Frequencies

GnomAD3 genomes

AF:

0.559

AC:

84775

AN:

151520

Hom.:

27157

Cov.:

show subpopulations

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:

AN:

Hom.:

Cov.:

AF XY:

0.500

AC XY:

AN XY:

show subpopulations

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

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.667

AC:

AN:

Other (OTH)

AC:

AN:

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.400

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.560

AC:

84893

AN:

151636

Hom.:

27212

Cov.:

AF XY:

0.566

AC XY:

41959

AN XY:

74068

show subpopulations

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1536

3072

4607

6143

7679

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.300

Hom.:

721

Bravo

AF:

0.592

Asia WGS

AF:

0.738

AC:

2545

AN:

3454

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Arginine:glycine amidinotransferase deficiency

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_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). -

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

2.3

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

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

Publications

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15-45361374-C-CTG

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over