chr3-49417868-GC-A

Variant names:

• chr3-49417868-GC-A
• rs386833692
• NM_000481.4:c.982_983delGCinsT

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000481.4(AMT):​c.982_983delGCinsT​(p.Ala328SerfsTer10) variant causes a frameshift, missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. A328T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: AMT NM_000481.4 frameshift, missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 8.97
• Publications: 0 publications found

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]

AMT Gene-Disease associations (from GenCC):

• glycine encephalopathy

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Myriad Women’s Health
• glycine encephalopathy 2

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
• infantile glycine encephalopathy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• neonatal glycine encephalopathy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• atypical glycine encephalopathy

  Inheritance: Unknown Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000283189 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 22 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-49417868-GC-A is Pathogenic according to our data. Variant chr3-49417868-GC-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 56241.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AMT	NM_000481.4	c.982_983delGCinsT	p.Ala328SerfsTer10	frameshift_variant, missense_variant	Exon 8 of 9	ENST00000273588.9	NP_000472.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AMT	ENST00000273588.9	c.982_983delGCinsT	p.Ala328SerfsTer10	frameshift_variant, missense_variant	Exon 8 of 9	1	NM_000481.4	ENSP00000273588.3
ENSG00000283189	ENST00000636166.1	c.1219_1220delGCinsT	p.Ala407SerfsTer10	frameshift_variant, missense_variant	Exon 10 of 11	5		ENSP00000490106.1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Glycine encephalopathy Pathogenic:3

-

Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jan 12, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 13, 2023

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: AMT c.982_983delinsT (p.Ala328SerfsX10) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic within ClinVar (e.g. c.1209del [p.Lys403fs], c.996dup [p.His333fs]). The variant was absent in 251188 control chromosomes (gnomAD). c.982_983delinsT has been reported in the literature in at least one compound heterozygous individual affected with Glycine Encephalopathy (Non-Ketotic Hyperglycinemia, Kure_2006). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One ClinVar submitter has assessed the variant since 2014: the variant was classified as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.0
Mutation Taster		=0/200	disease causing

Splicing

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

Other links and lift over

dbSNP: rs386833692; hg19: chr3-49455301;