3-49417964-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000481.4(AMT):c.887G>A(p.Arg296His) variant causes a missense change. The variant allele was found at a frequency of 0.00000686 in 1,458,732 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. R296C) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000069 (0 hom.)
• Consequence: AMT NM_000481.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 6.78

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 18 ACMG points.

• PM1: In a helix (size 5) in uniprot entity GCST_HUMAN there are 7 pathogenic changes around while only 1 benign (88%) 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 chr3-49417965-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 656955.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.943
• PP5: Variant 3-49417964-C-T is Pathogenic according to our data. Variant chr3-49417964-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 56239.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-49417964-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AMT	NM_000481.4	c.887G>A	p.Arg296His	missense_variant	8/9	ENST00000273588.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AMT	ENST00000273588.9	c.887G>A	p.Arg296His	missense_variant	8/9	1	NM_000481.4	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.0000330 AC: 8 AN: 242288 Hom.: 0 AF XY: 0.0000304 AC XY: 4 AN XY: 131728

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000889

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000277

Gnomad OTH exome AF: 0.000335

GnomAD4 exome AF: 0.00000686 AC: 10 AN: 1458732 Hom.: 0 Cov.: 33 AF XY: 0.00000689 AC XY: 5 AN XY: 725602

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000453

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000720

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.0000113

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Non-ketotic hyperglycinemia Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jun 17, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 21, 2022	Variant summary: AMT c.887G>A (p.Arg296His) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.3e-05 in 242288 control chromosomes. c.887G>A has been reported in the literature as homozygous and compound heterozygous genotypes in individuals affected with Glycine Encephalopathy (Non-Ketotic Hyperglycinemia) (example, Toone_2003, Coughlin_2017, Swanson_2015). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Suma Genomics	-	- -
Likely pathogenic, no assertion criteria provided	literature only	Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)	-	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Counsyl	Jun 02, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 23, 2021	This variant disrupts the p.Arg296 amino acid residue in AMT. Other variant(s) that disrupt this residue have been observed in individuals with AMT-related conditions (PMID: 12948742, 16450403, 26179960, 27362913, 28244183), which suggests that this may be a clinically significant amino acid residue. 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: 56239). This missense change has been observed in individual(s) with glycine encephalopathy or non-ketotic hyperglycinemia (PMID: 12948742, 16450403, 26179960, 27362913). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs386833690, gnomAD 0.009%). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 296 of the AMT protein (p.Arg296His). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 27, 2023	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 26179960, 34630504, 16051266, 16450403, 12948742, 27362913) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	AMT: PM3:Very Strong, PM2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.80
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.39
Cadd	Pathogenic	28
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.74	D;T;.;.;T;T;.;.;T;T;.;.
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.32	D
MetaRNN	Pathogenic	0.94	D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.81	D
MutationAssessor	Pathogenic	3.3	M;.;M;.;.;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-4.4	D;.;D;D;.;.;.;.;.;.;.;.
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D;.;D;D;.;.;.;.;.;.;.;.
Sift4G	Uncertain	0.049	D;.;D;T;.;.;.;.;.;.;.;.
Polyphen		1.0	D;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.88
MutPred		0.83		Loss of MoRF binding (P = 0.0452);.;Loss of MoRF binding (P = 0.0452);.;.;.;.;.;.;.;.;.;
MVP		0.95
MPC		0.82
ClinPred		0.98	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.97
gMVP		0.76

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: rs386833690; hg19: chr3-49455397; COSMIC: COSV104376793; COSMIC: COSV104376793;