Genetic Variant GAMT:p.Ala3Pro (chr19-1401470-C-G) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_000156.6(GAMT):c.7G>C(p.Ala3Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000827 in 1,209,714 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A3V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 8.3e-7 ( 0 hom. )

Consequence

GAMT
NM_000156.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.157

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: Orphanet, G2P, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics

GAMT links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.27182025).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GAMT	NM_000156.6 link	c.7G>C	p.Ala3Pro	missense_variant	Exon 1 of 6	ENST00000252288.8	NP_000147.1
GAMT	NM_138924.3 link	c.7G>C	p.Ala3Pro	missense_variant	Exon 1 of 5		NP_620279.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
GAMT	ENST00000252288.8 link	c.7G>C	p.Ala3Pro	missense_variant	Exon 1 of 6	1	NM_000156.6	ENSP00000252288.1
GAMT	ENST00000447102.8 link	c.7G>C	p.Ala3Pro	missense_variant	Exon 1 of 5	2		ENSP00000403536.2
GAMT	ENST00000640762.1 link	c.7G>C	p.Ala3Pro	missense_variant	Exon 1 of 6	5		ENSP00000492031.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

8.27e-7

AC:

AN:

1209714

Hom.:

Cov.:

AF XY:

0.00000170

AC XY:

AN XY:

588214

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000406

AC:

AN:

24634

American (AMR)

AF:

0.00

AC:

AN:

15338

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18430

East Asian (EAS)

AF:

0.00

AC:

AN:

27170

South Asian (SAS)

AF:

0.00

AC:

AN:

53504

European-Finnish (FIN)

AF:

0.00

AC:

AN:

29392

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3454

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

988406

Other (OTH)

AF:

0.00

AC:

AN:

49386

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

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

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.083

BayesDel_addAF

Uncertain

0.056

BayesDel_noAF

Benign

-0.16

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.37

T;.;.

Eigen

Benign

-0.41

Eigen_PC

Benign

-0.60

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.43

T;T;T

M_CAP

Pathogenic

0.94

MetaRNN

Benign

0.27

T;T;T

MetaSVM

Uncertain

0.029

MutationAssessor

Benign

1.6

L;.;L

PhyloP100

-0.16

PrimateAI

Uncertain

0.78

PROVEAN

Benign

-1.2

N;.;N

REVEL

Uncertain

0.30

Sift

Uncertain

0.029

D;.;D

Sift4G

Benign

0.065

T;.;D

Polyphen

0.95

P;.;.

Vest4

0.16

MutPred

0.21

Gain of glycosylation at A3 (P = 0.003);Gain of glycosylation at A3 (P = 0.003);Gain of glycosylation at A3 (P = 0.003);

MVP

0.94

MPC

0.37

ClinPred

0.48

GERP RS

1.3

PromoterAI

-0.024

Neutral

(source)

Varity_R

0.18

gMVP

0.52

Mutation Taster

=96/4

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over