rs1145086

Variant names:

• chr15-45362129-A-C
• rs1145086
• NM_001482.3:c.1252T>G

Your query was ambiguous. Multiple possible variants found:

• chr15-45362129-A-C
• chr15-45362129-A-G
• chr15-45362129-A-T

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1 PM2 PP3

The NM_001482.3(GATM):​c.1252T>G​(p.Leu418Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. L418L) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: GATM NM_001482.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.29
• Publications: 29 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: Uncertain_significance. The variant received 5 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 4 uncertain in NM_001482.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.777

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>G	p.Leu418Val	missense	Exon 9 of 9	NP_001473.1
	GATM	NM_001321015.2		c.865T>G	p.Leu289Val	missense	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.1252T>G	p.Leu418Val	missense	Exon 9 of 9	ENSP00000379895.3
	GATM	ENST00000558362.5	TSL:1	n.2908T>G		non_coding_transcript_exon	Exon 8 of 8
	GATM	ENST00000887717.1		c.1279T>G	p.Leu427Val	missense	Exon 9 of 9	ENSP00000557776.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 6.85e-7 AC: 1 AN: 1459824 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726448

African (AFR) AF: 0.00 AC: 0 AN: 33428

American (AMR) AF: 0.00 AC: 0 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.00 AC: 0 AN: 86190

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53400

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 9.01e-7 AC: 1 AN: 1110220

Other (OTH) AF: 0.00 AC: 0 AN: 60316

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.030
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.73	D
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.045	D
MetaRNN	Pathogenic	0.78	D
MetaSVM	Benign	-0.35	T
MutationAssessor	Pathogenic	3.1	M
PhyloP100		4.3
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-2.7	D
REVEL	Uncertain	0.36
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.012	D
Polyphen		0.97	D
Vest4		0.56
MutPred		0.56		Gain of sheet (P = 0.1208)
MVP		0.62
MPC		1.5
ClinPred		0.98	D
GERP RS		3.6
Varity_R		0.92
gMVP		0.85
Mutation Taster		=45/55	disease causing

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: rs1145086; hg19: chr15-45654327;