NM_001482.3:c.330A>T

Variant names:

• chr15-45369480-T-A
• rs1288775
• NM_001482.3:c.330A>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001482.3(GATM):​c.330A>T​(p.Gln110His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.328 in 1,613,390 control chromosomes in the GnomAD database, including 107,927 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. The gene GATM is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.46 (20539 hom., cov: 32)
  • Exomes 𝑓: 0.31 (87388 hom.)
• Consequence: GATM NM_001482.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:18
• Conservation: PhyloP100: 1.94
• Publications: 52 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=5.735975E-7).
• BP6: Variant 15-45369480-T-A is Benign according to our data. Variant chr15-45369480-T-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 129138.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.815 is higher than 0.05.

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.330A>T	p.Gln110His	missense	Exon 3 of 9	NP_001473.1	P50440-1
	GATM	NM_001321015.2		c.-58A>T		5_prime_UTR_premature_start_codon_gain	Exon 6 of 12	NP_001307944.1
	GATM	NM_001321015.2		c.-58A>T		5_prime_UTR	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.330A>T	p.Gln110His	missense	Exon 3 of 9	ENSP00000379895.3	P50440-1
	GATM	ENST00000558362.5	TSL:1	n.1986A>T		non_coding_transcript_exon	Exon 2 of 8
	GATM	ENST00000558537.5	TSL:4	c.-58A>T		5_prime_UTR_premature_start_codon_gain	Exon 3 of 3	ENSP00000453151.1	H0YLC6

Frequencies

GnomAD3 genomes AF: 0.461 AC: 70125 AN: 152004 Hom.: 20476 Cov.: 32

Gnomad AFR AF: 0.786

Gnomad AMI AF: 0.177

Gnomad AMR AF: 0.516

Gnomad ASJ AF: 0.349

Gnomad EAS AF: 0.836

Gnomad SAS AF: 0.409

Gnomad FIN AF: 0.308

Gnomad MID AF: 0.294

Gnomad NFE AF: 0.261

Gnomad OTH AF: 0.439

GnomAD2 exomes AF: 0.421 AC: 105856 AN: 251160 AF XY: 0.400

Gnomad AFR exome AF: 0.793

Gnomad AMR exome AF: 0.652

Gnomad ASJ exome AF: 0.352

Gnomad EAS exome AF: 0.830

Gnomad FIN exome AF: 0.313

Gnomad NFE exome AF: 0.269

Gnomad OTH exome AF: 0.367

GnomAD4 exome AF: 0.314 AC: 459387 AN: 1461268 Hom.: 87388 Cov.: 35 AF XY: 0.314 AC XY: 228182 AN XY: 726946

African (AFR) AF: 0.804 AC: 26896 AN: 33470

American (AMR) AF: 0.635 AC: 28413 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.349 AC: 9131 AN: 26130

East Asian (EAS) AF: 0.847 AC: 33601 AN: 39688

South Asian (SAS) AF: 0.389 AC: 33571 AN: 86242

European-Finnish (FIN) AF: 0.309 AC: 16525 AN: 53398

Middle Eastern (MID) AF: 0.363 AC: 2092 AN: 5768

European-Non Finnish (NFE) AF: 0.259 AC: 287810 AN: 1111472

Other (OTH) AF: 0.354 AC: 21348 AN: 60380

GnomAD4 genome AF: 0.462 AC: 70246 AN: 152122 Hom.: 20539 Cov.: 32 AF XY: 0.466 AC XY: 34627 AN XY: 74374

African (AFR) AF: 0.786 AC: 32637 AN: 41514

American (AMR) AF: 0.516 AC: 7887 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.349 AC: 1210 AN: 3470

East Asian (EAS) AF: 0.836 AC: 4329 AN: 5178

South Asian (SAS) AF: 0.408 AC: 1966 AN: 4824

European-Finnish (FIN) AF: 0.308 AC: 3250 AN: 10558

Middle Eastern (MID) AF: 0.306 AC: 90 AN: 294

European-Non Finnish (NFE) AF: 0.261 AC: 17773 AN: 67986

Other (OTH) AF: 0.446 AC: 943 AN: 2116

Alfa AF: 0.288 Hom.: 5456

Bravo AF: 0.497

TwinsUK AF: 0.254 AC: 943

ALSPAC AF: 0.259 AC: 997

ESP6500AA AF: 0.763 AC: 3354

ESP6500EA AF: 0.267 AC: 2297

ExAC AF: 0.418 AC: 50750

Asia WGS AF: 0.629 AC: 2183 AN: 3478

EpiCase AF: 0.277

EpiControl AF: 0.274

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	-	5	Arginine:glycine amidinotransferase deficiency (5)
-	-	3	not provided (3)
-	-	1	Fanconi renotubular syndrome 1 (1)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	11
DANN	Benign	0.77
DEOGEN2	Benign	0.26	T
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.51
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.040	T
MetaRNN	Benign	5.7e-7	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.63	N
PhyloP100		1.9
PrimateAI	Benign	0.34	T
PROVEAN	Benign	1.3	N
REVEL	Benign	0.078
Sift	Benign	0.56	T
Sift4G	Benign	0.54	T
Polyphen		0.0	B
Vest4		0.14
MutPred		0.12		Gain of disorder (P = 0.0912)
MPC		0.64
ClinPred		0.00063	T
GERP RS		3.5
Varity_R		0.054
gMVP		0.58
Mutation Taster		=99/1	polymorphism (auto)

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: rs1288775; hg19: chr15-45661678; COSMIC: COSV67540548; COSMIC: COSV67540548;