3-49419292-G-T

Position:

• chr3-49419292-G-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Moderate

The NM_000481.4(AMT):​c.664C>A​(p.Arg222Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R222C) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: AMT NM_000481.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.55

Genes affected

AMT (HGNC:473): (aminomethyltransferase) This gene encodes one of four critical components of the glycine cleavage system. Mutations in this gene have been associated with glycine encephalopathy. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2011]

ENSG00000283189 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PM1: In a strand (size 7) in uniprot entity GCST_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_000481.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-49419292-G-A is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.979
• PP5: Variant 3-49419292-G-T is Pathogenic according to our data. Variant chr3-49419292-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1469564.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AMT	NM_000481.4	c.664C>A	p.Arg222Ser	missense_variant	6/9	ENST00000273588.9	NP_000472.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AMT	ENST00000273588.9	c.664C>A	p.Arg222Ser	missense_variant	6/9	1	NM_000481.4	ENSP00000273588.3
ENSG00000283189	ENST00000636166.1	c.901C>A	p.Arg301Ser	missense_variant	8/11	5		ENSP00000490106.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Glycine encephalopathy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 22, 2023

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Arg222 amino acid residue in AMT. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 25231368, 26179960). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt AMT protein function. ClinVar contains an entry for this variant (Variation ID: 1469564). This variant has not been reported in the literature in individuals affected with AMT-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 222 of the AMT protein (p.Arg222Ser). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	D;.;.;D;T;T;.;.;D;T;.;.
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.98
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.70	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.95	D
MutationAssessor	Pathogenic	4.5	H;H;.;.;.;.;.;.;.;.;.;.
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-5.8	D;D;D;.;.;.;.;.;.;.;.;.
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D;D;D;.;.;.;.;.;.;.;.;.
Sift4G	Pathogenic	0.0010	D;D;D;.;.;.;.;.;.;.;.;.
Polyphen		1.0	D;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.95
MutPred		0.87		Gain of methylation at R219 (P = 0.0963);Gain of methylation at R219 (P = 0.0963);.;.;Gain of methylation at R219 (P = 0.0963);.;.;.;.;.;.;.;
MVP		0.96
MPC		0.85
ClinPred		1.0	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.99
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-49456725;