NM_000156.6:c.292C>T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM1

The NM_000156.6(GAMT):c.292C>T(p.Arg98Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000448 in 1,584,670 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R98Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000046 ( 0 hom. )

Consequence

GAMT
NM_000156.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:6

Conservation

PhyloP100: 0.723

Publications

0 publications found

Variant links:

Genes affected

GAMT (HGNC:4136): (guanidinoacetate N-methyltransferase) The protein encoded by this gene is a methyltransferase that converts guanidoacetate to creatine, using S-adenosylmethionine as the methyl donor. Defects in this gene have been implicated in neurologic syndromes and muscular hypotonia, probably due to creatine deficiency and accumulation of guanidinoacetate in the brain of affected individuals. Two transcript variants encoding different isoforms have been described for this gene. Pseudogenes of this gene are found on chromosomes 2 and 13. [provided by RefSeq, Feb 2012]

GAMT Gene-Disease associations (from GenCC):

guanidinoacetate methyltransferase deficiency
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, G2P, ClinGen, Labcorp Genetics (formerly Invitae)

GAMT links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 16 uncertain in NM_000156.6

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000156.6. 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
	GAMT	NM_000156.6	MANE Select	c.292C>T	p.Arg98Trp	missense	Exon 2 of 6	NP_000147.1	Q14353-1
	GAMT	NM_138924.3		c.292C>T	p.Arg98Trp	missense	Exon 2 of 5	NP_620279.1	Q14353-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GAMT	ENST00000252288.8	TSL:1 MANE Select	c.292C>T	p.Arg98Trp	missense	Exon 2 of 6	ENSP00000252288.1	Q14353-1
GAMT	ENST00000902474.1		c.562C>T	p.Arg188Trp	missense	Exon 2 of 6	ENSP00000572533.1
GAMT	ENST00000447102.8	TSL:2	c.292C>T	p.Arg98Trp	missense	Exon 2 of 5	ENSP00000403536.2	Q14353-2

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000690

AC:

AN:

202910

AF XY:

0.0000639

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000134

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000261

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000453

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000461

AC:

AN:

1432500

Hom.:

Cov.:

AF XY:

0.0000493

AC XY:

AN XY:

710144

show subpopulations

African (AFR)

AF:

0.0000304

AC:

AN:

32892

American (AMR)

AF:

0.0000982

AC:

AN:

40724

Ashkenazi Jewish (ASJ)

AF:

0.0000392

AC:

AN:

25518

East Asian (EAS)

AF:

0.000392

AC:

AN:

38222

South Asian (SAS)

AF:

0.0000608

AC:

AN:

82292

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49634

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5732

European-Non Finnish (NFE)

AF:

0.0000364

AC:

AN:

1098206

Other (OTH)

AF:

0.00

AC:

AN:

59280

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152170

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74330

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41438

American (AMR)

AF:

0.00

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.000207

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

68028

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.515

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000103

Hom.:

Bravo

AF:

0.0000529

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.0000582

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Cerebral creatine deficiency syndrome (1)

Deficiency of guanidinoacetate methyltransferase (1)

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.35

BayesDel_addAF

Pathogenic

0.27

BayesDel_noAF

Pathogenic

0.14

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.88

Eigen

Uncertain

0.53

Eigen_PC

Uncertain

0.43

FATHMM_MKL

Uncertain

0.89

LIST_S2

Uncertain

0.96

M_CAP

Pathogenic

0.62

MetaRNN

Uncertain

0.60

MetaSVM

Pathogenic

0.80

MutationAssessor

Pathogenic

3.4

PhyloP100

0.72

PrimateAI

Uncertain

0.62

PROVEAN

Pathogenic

-5.3

REVEL

Pathogenic

0.77

Sift

Uncertain

0.0060

Sift4G

Uncertain

0.0090

Polyphen

1.0

Vest4

0.93

MutPred

0.50

Loss of catalytic residue at R98 (P = 0.0336)

MVP

0.95

MPC

0.64

ClinPred

0.72

GERP RS

3.1

PromoterAI

0.0091

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.53

gMVP

0.87

Mutation Taster

=20/80

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over