rs1126422

chr3-49421551-G-A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_000481.4(AMT):c.280C>T(p.Arg94Trp) variant causes a missense change. The variant allele was found at a frequency of 0.0000212 in 1,461,846 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R94Q) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: AMT NM_000481.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 3.71

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]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PM1: In a helix (size 7) in uniprot entity GCST_HUMAN there are 6 pathogenic changes around while only 1 benign (86%) 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 chr3-49421550-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2040004.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.919
• PP5: Variant 3-49421551-G-A is Pathogenic according to our data. Variant chr3-49421551-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 557814.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-49421551-G-A is described in Lovd as [Pathogenic]. Variant chr3-49421551-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AMT	NM_000481.4	c.280C>T	p.Arg94Trp	missense_variant	3/9	ENST00000273588.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AMT	ENST00000273588.9	c.280C>T	p.Arg94Trp	missense_variant	3/9	1	NM_000481.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000398 AC: 10 AN: 251486 Hom.: 0 AF XY: 0.0000294 AC XY: 4 AN XY: 135918

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000212 AC: 31 AN: 1461846 Hom.: 0 Cov.: 30 AF XY: 0.0000138 AC XY: 10 AN XY: 727228

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000134

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000180

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Non-ketotic hyperglycinemia Pathogenic:5

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Jun 24, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Apr 07, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Nov 18, 2023	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 94 of the AMT protein (p.Arg94Trp). This variant is present in population databases (rs1126422, gnomAD 0.009%). This missense change has been observed in individual(s) with non-ketotic hyperglycinemia (PMID: 26179960, 27362913, 28244183). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 557814). 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 with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	May 15, 2020	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.58
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Pathogenic	0.30
Cadd	Pathogenic	33
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.92	D;.;.;D;T;T;T;.;D;.;.
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.92	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.67	D
MutationAssessor	Pathogenic	3.0	M;M;M;.;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-5.5	D;D;D;.;.;.;.;.;.;.;.
REVEL	Pathogenic	0.82
Sift	Benign	0.060	T;D;T;.;.;.;.;.;.;.;.
Sift4G	Benign	0.086	T;T;T;.;.;.;.;.;.;.;.
Polyphen		1.0	D;.;.;.;.;.;.;.;.;.;.
Vest4		0.64
MutPred		0.81		Loss of disorder (P = 0.0957);Loss of disorder (P = 0.0957);Loss of disorder (P = 0.0957);.;Loss of disorder (P = 0.0957);.;Loss of disorder (P = 0.0957);.;.;.;.;
MVP		0.98
MPC		0.81
ClinPred		0.95	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.90
gMVP		0.88

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

LitVar

Other links and lift over

dbSNP: rs1126422; hg19: chr3-49458984;