15-45362081-G-A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The ENST00000558362.5(GATM):​n.2956C>T variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000633 in 1,391,220 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.00034 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00067 ( 7 hom. )

Consequence

GATM
ENST00000558362.5 non_coding_transcript_exon

Scores

2

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 2.36

Publications

0 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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.79).
BS1
Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000341 (52/152270) while in subpopulation SAS AF = 0.0108 (52/4826). AF 95% confidence interval is 0.00844. There are 0 homozygotes in GnomAd4. There are 41 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
BS2
High Homozygotes in GnomAdExome4 at 7 AR,AD gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
GATMNM_001482.3 linkc.*28C>T 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
GATMENST00000396659.8 linkc.*28C>T 3_prime_UTR_variant Exon 9 of 9 1 NM_001482.3 ENSP00000379895.3 P50440-1

Frequencies

GnomAD3 genomes
AF:
0.000335
AC:
51
AN:
152152
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.0106
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.00125
AC:
314
AN:
250458
AF XY:
0.00173
show subpopulations
Gnomad AFR exome
AF:
0.0000617
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000177
Gnomad OTH exome
AF:
0.000492
GnomAD4 exome
AF:
0.000668
AC:
828
AN:
1238950
Hom.:
7
Cov.:
18
AF XY:
0.000971
AC XY:
609
AN XY:
627406
show subpopulations
African (AFR)
AF:
0.0000714
AC:
2
AN:
28026
American (AMR)
AF:
0.0000225
AC:
1
AN:
44406
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
24720
East Asian (EAS)
AF:
0.00
AC:
0
AN:
38426
South Asian (SAS)
AF:
0.00960
AC:
781
AN:
81344
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53218
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5342
European-Non Finnish (NFE)
AF:
0.0000143
AC:
13
AN:
910626
Other (OTH)
AF:
0.000587
AC:
31
AN:
52842
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.474
Heterozygous variant carriers
0
46
92
137
183
229
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
20
40
60
80
100
<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:
0.000341
AC:
52
AN:
152270
Hom.:
0
Cov.:
32
AF XY:
0.000551
AC XY:
41
AN XY:
74470
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
41538
American (AMR)
AF:
0.00
AC:
0
AN:
15288
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3472
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5180
South Asian (SAS)
AF:
0.0108
AC:
52
AN:
4826
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10624
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
294
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
68020
Other (OTH)
AF:
0.00
AC:
0
AN:
2116
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.506
Heterozygous variant carriers
0
3
6
10
13
16
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<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:
0.000108
Hom.:
0
Bravo
AF:
0.0000718
Asia WGS
AF:
0.00664
AC:
23
AN:
3478

ClinVar

Significance: Likely benign
Submissions summary: Benign:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Arginine:glycine amidinotransferase deficiency Benign:1
Jan 12, 2018
Illumina Laboratory Services, Illumina
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

not provided Benign:1
Jun 14, 2018
GeneDx
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.79
CADD
Benign
15
DANN
Benign
0.83
PhyloP100
2.4
Mutation Taster
=100/0
polymorphism

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

Other links and lift over

dbSNP: rs570994409; hg19: chr15-45654279; API