15-45362129-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BA1BP4BP7

This summary comes from the ClinGen Evidence Repository: The NM_001482.3:c.1252T>C (p.Leu418=) variant in GATM is a synonymous (silent) variant that is not predicted by SpliceAI to impact splicing. In addition, it occurs at a nucleotide that is not conserved as shown by PhyloP (BP7). The highest population minor allele frequency in gnomAD v2.1.1 is 0.9186 (18317/19940 alleles) in the East Asian population, which is higher than the ClinGen CCDS VCEP’s threshold for BA1 (>0.0005), and therefore meets this criterion (BA1). The computational splicing predictor SpliceAI gives a score of 0.0 for donor and acceptor loss suggesting that the variant has no impact on splicing, and the nucleotide is not highly conserved (BP4, BP7). There is a ClinVar entry for this variant (Variation ID: 129137). 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, BP4, BP7.(Classification approved by the ClinGen CCDS VCEP on June 6, 2022). LINK:https://erepo.genome.network/evrepo/ui/classification/CA152946/MONDO:0012996/025

Frequency

Genomes: 𝑓 0.56 ( 27386 hom., cov: 31)

Exomes 𝑓: 0.43 ( 149264 hom. )

Consequence

GATM
NM_001482.3 synonymous

Scores

Clinical Significance

Benign reviewed by expert panel B:16

Conservation

PhyloP100: 4.29

Publications

29 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 -10 ACMG points.

BP4

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

BP7

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

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.1252T>C	p.Leu418Leu	synonymous	Exon 9 of 9	NP_001473.1
	GATM	NM_001321015.2		c.865T>C	p.Leu289Leu	synonymous	Exon 12 of 12	NP_001307944.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
GATM	ENST00000396659.8	TSL:1 MANE Select	c.1252T>C	p.Leu418Leu	synonymous	Exon 9 of 9	ENSP00000379895.3
GATM	ENST00000558362.5	TSL:1	n.2908T>C		non_coding_transcript_exon	Exon 8 of 8
GATM	ENST00000887717.1		c.1279T>C	p.Leu427Leu	synonymous	Exon 9 of 9	ENSP00000557776.1

Frequencies

GnomAD3 genomes

AF:

0.560

AC:

85103

AN:

151898

Hom.:

27327

Cov.:

show subpopulations

Gnomad AFR

AF:

0.842

Gnomad AMI

AF:

0.235

Gnomad AMR

AF:

0.619

Gnomad ASJ

AF:

0.534

Gnomad EAS

AF:

0.908

Gnomad SAS

AF:

0.594

Gnomad FIN

AF:

0.409

Gnomad MID

AF:

0.551

Gnomad NFE

AF:

0.376

Gnomad OTH

AF:

0.556

GnomAD2 exomes

AF:

0.536

AC:

134200

AN:

250570

AF XY:

0.520

show subpopulations

Gnomad AFR exome

AF:

0.850

Gnomad AMR exome

AF:

0.720

Gnomad ASJ exome

AF:

0.534

Gnomad EAS exome

AF:

0.919

Gnomad FIN exome

AF:

0.420

Gnomad NFE exome

AF:

0.387

Gnomad OTH exome

AF:

0.482

GnomAD4 exome

AF:

0.431

AC:

627625

AN:

1457486

Hom.:

149264

Cov.:

AF XY:

0.433

AC XY:

313857

AN XY:

725416

show subpopulations

African (AFR)

AF:

0.861

AC:

28749

AN:

33400

American (AMR)

AF:

0.705

AC:

31524

AN:

44698

Ashkenazi Jewish (ASJ)

AF:

0.536

AC:

14004

AN:

26104

East Asian (EAS)

AF:

0.931

AC:

36923

AN:

39678

South Asian (SAS)

AF:

0.566

AC:

48739

AN:

86110

European-Finnish (FIN)

AF:

0.413

AC:

22039

AN:

53386

Middle Eastern (MID)

AF:

0.559

AC:

3217

AN:

5752

European-Non Finnish (NFE)

AF:

0.373

AC:

413855

AN:

1108118

Other (OTH)

AF:

0.474

AC:

28575

AN:

60240

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

16028

32057

48085

64114

80142

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

13488

26976

40464

53952

67440

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.561

AC:

85226

AN:

152016

Hom.:

27386

Cov.:

AF XY:

0.567

AC XY:

42152

AN XY:

74294

show subpopulations

African (AFR)

AF:

0.842

AC:

34943

AN:

41492

American (AMR)

AF:

0.620

AC:

9471

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.534

AC:

1853

AN:

3470

East Asian (EAS)

AF:

0.909

AC:

4688

AN:

5160

South Asian (SAS)

AF:

0.592

AC:

2850

AN:

4812

European-Finnish (FIN)

AF:

0.409

AC:

4304

AN:

10528

Middle Eastern (MID)

AF:

0.558

AC:

164

AN:

294

European-Non Finnish (NFE)

AF:

0.376

AC:

25556

AN:

67962

Other (OTH)

AF:

0.560

AC:

1183

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1543

3085

4628

6170

7713

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

694

1388

2082

2776

3470

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.478

Hom.:

14826

Bravo

AF:

0.592

Asia WGS

AF:

0.741

AC:

2573

AN:

3478

EpiCase

AF:

0.396

EpiControl

AF:

0.395

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

Arginine:glycine amidinotransferase deficiency (5)

not specified (5)

not provided (4)

Fanconi renotubular syndrome 1 (1)

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.53

CADD

Benign

8.5

(source)

DANN

Benign

0.72

PhyloP100

4.3

Mutation Taster

=98/2

polymorphism (auto)

(source)

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over