3-49422145-G-C

Variant names:

• chr3-49422145-G-C
• NM_000481.4:c.217C>G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2 PM5 PP3_Strong PP5_Moderate

The NM_000481.4(AMT):​c.217C>G​(p.Arg73Gly) variant causes a missense change. 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. R73C) 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: 5.84

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:):

NICN1 (HGNC:18317): (nicolin 1, tubulin polyglutamylase complex subunit) This protein encoded by this gene localizes to the nucleus and is expressed in numerous tissues including brain, testis, liver, and kidney. This refseq contains genomic sequence in its 3' UTR which is not supported by experimental evidence. Computer predictions indicate that this region of the 3' UTR contains hairpin-forming self-complementary sequence which is possibly excised after transcription. This gene has a pseudogene on chromosome X. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-49422145-G-A is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.985
• PP5: Variant 3-49422145-G-C is Pathogenic according to our data. Variant chr3-49422145-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2912348.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AMT	NM_000481.4	c.217C>G	p.Arg73Gly	missense_variant	Exon 2 of 9	ENST00000273588.9	NP_000472.2
NICN1	NM_032316.3	c.*2688C>G		downstream_gene_variant		ENST00000273598.8	NP_115692.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AMT	ENST00000273588.9	c.217C>G	p.Arg73Gly	missense_variant	Exon 2 of 9	1	NM_000481.4	ENSP00000273588.3
ENSG00000283189	ENST00000636166.1	c.496-573C>G		intron_variant	Intron 4 of 10	5		ENSP00000490106.1
NICN1	ENST00000273598.8	c.*2688C>G		downstream_gene_variant		1	NM_032316.3	ENSP00000273598.4

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

Jun 24, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 glycine, which is neutral and non-polar, at codon 73 of the AMT protein (p.Arg73Gly). This variant disrupts the p.Arg73 amino acid residue in AMT. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16450403, 27362913). 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. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	D;T;.;.;D;D;T;D;.;.;D;D
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	1.0	D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.38	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.74	D
MutationAssessor	Pathogenic	4.4	H;.;H;H;.;.;.;.;.;.;.;.
PrimateAI	Uncertain	0.53	T
PROVEAN	Pathogenic	-6.2	D;.;D;D;.;.;.;.;.;.;.;.
REVEL	Pathogenic	0.86
Sift	Pathogenic	0.0	D;.;D;D;.;.;.;.;.;.;.;.
Sift4G	Uncertain	0.0030	D;.;D;D;.;.;.;.;.;.;.;.
Polyphen		1.0	D;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.89
MutPred		0.92		Loss of catalytic residue at R73 (P = 0.0291);Loss of catalytic residue at R73 (P = 0.0291);Loss of catalytic residue at R73 (P = 0.0291);Loss of catalytic residue at R73 (P = 0.0291);.;Loss of catalytic residue at R73 (P = 0.0291);.;Loss of catalytic residue at R73 (P = 0.0291);.;Loss of catalytic residue at R73 (P = 0.0291);.;Loss of catalytic residue at R73 (P = 0.0291);
MVP		0.95
MPC		0.91
ClinPred		1.0	D
GERP RS		4.5
Varity_R		0.98
gMVP		0.91

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: chr3-49459578;