rs148564534

Variant names:

• chr15-45369403-G-A
• rs148564534
• NM_001482.3:c.407C>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4 BS3_Supporting BA1

This summary comes from the ClinGen Evidence Repository: The NM_001482.3:c.407C>T variant in GATM is a missense variant predicted to cause substitution of threonine by methionine at amino acid 136 (p.Thr136Met). The highest population minor allele frequency in gnomAD v2.1.1 is 0.0007357 (95/129130 alleles) in the non-Finnish European population, which is higher than the ClinGen CCDS VCEP’s threshold for BA1 (>0.0005), and therefore meets this criterion (BA1). Expression of the variant in HeLa cells resulted in >50% wild type AGAT activity suggesting that this variant does not significantly impact protein function (PMID:27233232) (BS3_Supporting). The computational predictor REVEL gives a score of 0.049 which is below the threshold of 0.15, evidence that does not predict a damaging effect on AGAT function (BP4). There is a ClinVar entry for this variant (Variation ID: 205613). 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 1.0): BA1, BS3_Supporting, BP4.(Classification approved by the ClinGen CCDS VCEP on January 25, 2023). LINK:https://erepo.genome.network/evrepo/ui/classification/CA314868/MONDO:0012996/025

• Frequency:
  • Genomes: 𝑓 0.00059 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00059 (3 hom.)
• Consequence: GATM NM_001482.3 missense
• Clinical Significance: Benign reviewed by expert panel U:2 B:7
• Conservation: PhyloP100: 0.773
• Publications: 6 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: Orphanet, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, ClinGen
• Fanconi renotubular syndrome 1

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• primary Fanconi syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Specifications for GATM are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: For more information check the summary or visit ClinGen Evidence Repository.
• BS3: 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.407C>T	p.Thr136Met	missense	Exon 3 of 9	NP_001473.1	P50440-1
	GATM	NM_001321015.2		c.20C>T	p.Thr7Met	missense	Exon 6 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.407C>T	p.Thr136Met	missense	Exon 3 of 9	ENSP00000379895.3	P50440-1
	GATM	ENST00000558362.5	TSL:1	n.2063C>T		non_coding_transcript_exon	Exon 2 of 8
	GATM	ENST00000887717.1		c.407C>T	p.Thr136Met	missense	Exon 3 of 9	ENSP00000557776.1

Frequencies

GnomAD3 genomes AF: 0.000585 AC: 89 AN: 152126 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.0274

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000779

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000370 AC: 93 AN: 251392 AF XY: 0.000420

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000765

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000587 AC: 858 AN: 1461806 Hom.: 3 Cov.: 31 AF XY: 0.000589 AC XY: 428 AN XY: 727204

African (AFR) AF: 0.000179 AC: 6 AN: 33478

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39690

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86256

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000734 AC: 816 AN: 1111952

Other (OTH) AF: 0.000513 AC: 31 AN: 60390

GnomAD4 genome AF: 0.000585 AC: 89 AN: 152126 Hom.: 2 Cov.: 32 AF XY: 0.000579 AC XY: 43 AN XY: 74316

African (AFR) AF: 0.000193 AC: 8 AN: 41436

American (AMR) AF: 0.000197 AC: 3 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10594

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000779 AC: 53 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2084

Alfa AF: 0.000602 Hom.: 0

Bravo AF: 0.000623

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000582 AC: 5

ExAC AF: 0.000321 AC: 39

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000545

EpiControl AF: 0.000711

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	1	2	Arginine:glycine amidinotransferase deficiency (3)
-	1	2	not provided (3)
-	-	1	Inborn genetic diseases (1)
-	-	1	Intellectual disability (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.050
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	15
DANN	Benign	0.86
DEOGEN2	Benign	0.31	T
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.46
FATHMM_MKL	Benign	0.39	N
LIST_S2	Benign	0.56	T
M_CAP	Benign	0.0027	T
MetaRNN	Benign	0.0070	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.46	N
PhyloP100		0.77
PrimateAI	Benign	0.31	T
PROVEAN	Benign	0.080	N
REVEL	Benign	0.049
Sift	Benign	0.12	T
Sift4G	Benign	0.14	T
Polyphen		0.0	B
Vest4		0.20
MVP		0.15
MPC		0.71
ClinPred		0.024	T
GERP RS		2.3
Varity_R		0.032
gMVP		0.49
Mutation Taster		=97/3	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: rs148564534; hg19: chr15-45661601; COSMIC: COSV101188036; COSMIC: COSV101188036;