chr15-45361984-C-T

Variant names:

• chr15-45361984-C-T
• rs143689218
• ENST00000558362.5:n.3053G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The ENST00000558362.5(GATM):​n.3053G>A 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 0.00251 in 700,724 control chromosomes in the GnomAD database, including 14 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 0.0069 (9 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (5 hom.)
• Consequence: GATM ENST00000558362.5 non_coding_transcript_exon
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.472
• Publications: 2 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: 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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00692 (1054/152244) while in subpopulation AFR AF = 0.0224 (930/41536). AF 95% confidence interval is 0.0212. There are 9 homozygotes in GnomAd4. There are 467 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 9 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GATM	NM_001482.3	c.*125G>A		3_prime_UTR_variant	Exon 9 of 9	ENST00000396659.8	NP_001473.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GATM	ENST00000396659.8	c.*125G>A		3_prime_UTR_variant	Exon 9 of 9	1	NM_001482.3	ENSP00000379895.3

Frequencies

GnomAD3 genomes AF: 0.00695 AC: 1057 AN: 152126 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.0225

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00491

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000470

Gnomad OTH AF: 0.00669

GnomAD4 exome AF: 0.00129 AC: 705 AN: 548480 Hom.: 5 Cov.: 5 AF XY: 0.00106 AC XY: 312 AN XY: 294938

African (AFR) AF: 0.0247 AC: 377 AN: 15236

American (AMR) AF: 0.00272 AC: 89 AN: 32662

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19372

East Asian (EAS) AF: 0.00 AC: 0 AN: 31942

South Asian (SAS) AF: 0.0000648 AC: 4 AN: 61708

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38840

Middle Eastern (MID) AF: 0.00584 AC: 22 AN: 3770

European-Non Finnish (NFE) AF: 0.000362 AC: 114 AN: 314816

Other (OTH) AF: 0.00329 AC: 99 AN: 30134

GnomAD4 genome AF: 0.00692 AC: 1054 AN: 152244 Hom.: 9 Cov.: 32 AF XY: 0.00627 AC XY: 467 AN XY: 74442

African (AFR) AF: 0.0224 AC: 930 AN: 41536

American (AMR) AF: 0.00491 AC: 75 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000471 AC: 32 AN: 68012

Other (OTH) AF: 0.00662 AC: 14 AN: 2114

Alfa AF: 0.00606 Hom.: 2

Bravo AF: 0.00787

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Arginine:glycine amidinotransferase deficiency Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: 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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

Jul 09, 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	-0.49
CADD	Benign	4.4
DANN	Benign	0.58
PhyloP100		0.47
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

Other links and lift over

dbSNP: rs143689218; hg19: chr15-45654182;