rs121964983

Variant names:

• chr3-49422237-T-C
• rs121964983
• NM_000481.4:c.125A>G

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_000481.4(AMT):​c.125A>G​(p.His42Arg) 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 (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: AMT NM_000481.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3 O:1
• Conservation: PhyloP100: 4.70

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 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.987
• PP5: Variant 3-49422237-T-C is Pathogenic according to our data. Variant chr3-49422237-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 11976.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-49422237-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AMT	NM_000481.4	c.125A>G	p.His42Arg	missense_variant	Exon 2 of 9	ENST00000273588.9	NP_000472.2
NICN1	NM_032316.3	c.*2596A>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.125A>G	p.His42Arg	missense_variant	Exon 2 of 9	1	NM_000481.4	ENSP00000273588.3
ENSG00000283189	ENST00000636166.1	c.496-665A>G		intron_variant	Intron 4 of 10	5		ENSP00000490106.1
NICN1	ENST00000273598.8	c.*2596A>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: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Glycine encephalopathy Pathogenic:1 Other:1

Aug 16, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: AMT c.125A>G (p.His42Arg) results in a non-conservative amino acid change located in the Aminomethyltransferase, folate-binding domain (IPR006222) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251328 control chromosomes. c.125A>G has been reported in the literature in multiple individuals, including at least 5 members of a large family affected with Glycine Encephalopathy (Non-Ketotic Hyperglycinemia) (e.g., Kure_1998). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 9600239). ClinVar contains an entry for this variant (Variation ID: 11976). Based on the evidence outlined above, the variant was classified as pathogenic. -

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GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Glycine encephalopathy 2 Pathogenic:1

Apr 01, 1998

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Glycine encephalopathy 1 Pathogenic:1

Nov 08, 2023

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.94	D;T;.;.;T;D;.;T
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.60	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.57	D
MutationAssessor	Pathogenic	4.4	H;.;H;H;.;.;.;.
PrimateAI	Uncertain	0.79	T
PROVEAN	Pathogenic	-6.9	D;.;D;D;.;.;.;.
REVEL	Pathogenic	0.83
Sift	Uncertain	0.0010	D;.;D;D;.;.;.;.
Sift4G	Pathogenic	0.0010	D;.;D;D;.;.;.;.
Polyphen		1.0	D;.;.;.;.;.;.;.
Vest4		0.97
MutPred		0.93		Gain of methylation at H42 (P = 0.0353);Gain of methylation at H42 (P = 0.0353);Gain of methylation at H42 (P = 0.0353);Gain of methylation at H42 (P = 0.0353);Gain of methylation at H42 (P = 0.0353);Gain of methylation at H42 (P = 0.0353);Gain of methylation at H42 (P = 0.0353);Gain of methylation at H42 (P = 0.0353);
MVP		0.95
MPC		0.89
ClinPred		1.0	D
GERP RS		2.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.98
gMVP		0.93

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

Publications

LitVar

Other links and lift over

dbSNP: rs121964983; hg19: chr3-49459670;