19-1401470-C-A

Variant names:

• chr19-1401470-C-A
• rs574164748
• NM_000156.6:c.7G>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Moderate BP6_Moderate

The NM_000156.6(GAMT):​c.7G>T​(p.Ala3Ser) 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. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). 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
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.157
• Publications: 2 publications found

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

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14780992).
• BP6: Variant 19-1401470-C-A is Benign according to our data. Variant chr19-1401470-C-A is described in ClinVar as Likely_benign. ClinVar VariationId is 205575.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GAMT	NM_000156.6	c.7G>T	p.Ala3Ser	missense_variant	Exon 1 of 6	ENST00000252288.8	NP_000147.1
GAMT	NM_138924.3	c.7G>T	p.Ala3Ser	missense_variant	Exon 1 of 5		NP_620279.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GAMT	ENST00000252288.8	c.7G>T	p.Ala3Ser	missense_variant	Exon 1 of 6	1	NM_000156.6	ENSP00000252288.1
GAMT	ENST00000447102.8	c.7G>T	p.Ala3Ser	missense_variant	Exon 1 of 5	2		ENSP00000403536.2
GAMT	ENST00000640762.1	c.7G>T	p.Ala3Ser	missense_variant	Exon 1 of 6	5		ENSP00000492031.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 8.27e-7 AC: 1 AN: 1209714 Hom.: 0 Cov.: 31 AF XY: 0.00000170 AC XY: 1 AN XY: 588214

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

African (AFR) AF: 0.00 AC: 0 AN: 24634

American (AMR) AF: 0.00 AC: 0 AN: 15338

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18430

East Asian (EAS) AF: 0.00 AC: 0 AN: 27170

South Asian (SAS) AF: 0.0000187 AC: 1 AN: 53504

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 29392

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3454

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 988406

Other (OTH) AF: 0.00 AC: 0 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.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Aug 08, 2013

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.020	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	5.8
DANN	Benign	0.95
DEOGEN2	Benign	0.32	T;.;.
Eigen	Benign	-0.92
Eigen_PC	Benign	-0.97
FATHMM_MKL	Benign	0.081	N
LIST_S2	Benign	0.35	T;T;T
M_CAP	Pathogenic	0.89	D
MetaRNN	Benign	0.15	T;T;T
MetaSVM	Benign	-0.40	T
MutationAssessor	Benign	0.14	N;.;N
PhyloP100		-0.16
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-0.63	N;.;N
REVEL	Benign	0.22
Sift	Benign	0.43	T;.;T
Sift4G	Benign	0.32	T;.;T
Polyphen		0.0030	B;.;.
Vest4		0.14
MutPred		0.079		Gain of glycosylation at A3 (P = 0.0018);Gain of glycosylation at A3 (P = 0.0018);Gain of glycosylation at A3 (P = 0.0018);
MVP		0.80
MPC		0.14
ClinPred		0.11	T
GERP RS		1.3
PromoterAI		0.13	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.071
gMVP		0.45
Mutation Taster		=98/2	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: rs574164748; hg19: chr19-1401469;