NM_001482.3:c.511A>T

Variant names:

• chr15-45368234-T-A
• rs747203599
• NM_001482.3:c.511A>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001482.3(GATM):​c.511A>T​(p.Ile171Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GATM NM_001482.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.58
• Publications: 0 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.511A>T	p.Ile171Phe	missense	Exon 4 of 9	NP_001473.1
	GATM	NM_001321015.2		c.124A>T	p.Ile42Phe	missense	Exon 7 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.511A>T	p.Ile171Phe	missense	Exon 4 of 9	ENSP00000379895.3
	GATM	ENST00000558362.5	TSL:1	n.2167A>T		non_coding_transcript_exon	Exon 3 of 8
	GATM	ENST00000887717.1		c.538A>T	p.Ile180Phe	missense	Exon 4 of 9	ENSP00000557776.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Arginine:glycine amidinotransferase deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.61
BayesDel_addAF	Uncertain	0.038	T
BayesDel_noAF	Uncertain	-0.010
CADD	Benign	23
DANN	Benign	0.97
DEOGEN2	Uncertain	0.43	T
Eigen	Benign	0.072
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.023	T
MetaRNN	Uncertain	0.52	D
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	2.0	M
PhyloP100		7.6
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.25
Sift	Benign	0.27	T
Sift4G	Benign	0.55	T
Polyphen		0.18	B
Vest4		0.86
MutPred		0.55		Loss of sheet (P = 0.1398)
MVP		0.54
MPC		1.1
ClinPred		0.53	D
GERP RS		5.4
Varity_R		0.50
gMVP		0.92

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: rs747203599; hg19: chr15-45660432;