Genetic Variant NM_001482.3:c.68G>A (chr15-45378386-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001482.3(GATM):c.68G>A(p.Arg23Gln) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R23P) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

GATM
NM_001482.3 missense, splice_region

Scores

Splicing: ADA: 0.1054

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.89

Publications

1 publications found

Variant links:

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

GATM links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.23839).

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.68G>A	p.Arg23Gln	missense splice_region	Exon 1 of 9	NP_001473.1	P50440-1
	GATM	NM_001321015.2		c.-318-1567G>A		intron	N/A	NP_001307944.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GATM	ENST00000396659.8	TSL:1 MANE Select	c.68G>A	p.Arg23Gln	missense splice_region	Exon 1 of 9	ENSP00000379895.3	P50440-1
GATM	ENST00000558362.5	TSL:1	n.159G>A		non_coding_transcript_exon	Exon 1 of 8
GATM	ENST00000887717.1		c.68G>A	p.Arg23Gln	missense splice_region	Exon 1 of 9	ENSP00000557776.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1367800

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

674750

African (AFR)

AF:

0.00

AC:

AN:

29420

American (AMR)

AF:

0.00

AC:

AN:

34230

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24482

East Asian (EAS)

AF:

0.00

AC:

AN:

33860

South Asian (SAS)

AF:

0.00

AC:

AN:

77164

European-Finnish (FIN)

AF:

0.00

AC:

AN:

34300

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4826

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1072326

Other (OTH)

AF:

0.00

AC:

AN:

57192

GnomAD4 genome

Cov.:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000136

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.40

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.32

Eigen

Benign

-0.14

Eigen_PC

Benign

0.0082

FATHMM_MKL

Benign

0.61

LIST_S2

Benign

0.82

M_CAP

Uncertain

0.16

MetaRNN

Benign

0.24

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.1

PhyloP100

1.9

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-0.47

REVEL

Benign

0.026

Sift

Benign

0.19

Sift4G

Benign

0.41

Polyphen

0.14

Vest4

0.14

MVP

0.36

MPC

0.79

ClinPred

0.79

GERP RS

4.5

PromoterAI

0.078

Neutral

(source)

Varity_R

0.074

gMVP

0.50

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.11

dbscSNV1_RF

Benign

0.43

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over