3-49422364-TGCGCAACTAAGTGGACGACACAAGGCCGGGGGGAATGCCTGCAGGCGAAAGCCCAGACGGGCCACCACACTTACAGCCCTCTGCATCGTCGCCTGCAACGAGTGCAGACG-T

Variant names:

• chr3-49422364-TGCGCAACTAAGTGGACGACACAAGGCCGGGGGGAATGCCTGCAGGCGAAAGCCCAGACGGGCCACCACACTTACAGCCCTCTGCATCGTCGCCTGCAACGAGTGCAGACG-T
• rs2049123051
• NM_000481.4:c.-24_86del

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP5_Moderate

The NM_000481.4(AMT):​c.-24_86del variant causes a 5 prime UTR truncation, exon loss change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: AMT NM_000481.4 5_prime_UTR_truncation, exon_loss
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 2.41

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]

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]

ENSG00000283189 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-49422364-TGCGCAACTAAGTGGACGACACAAGGCCGGGGGGAATGCCTGCAGGCGAAAGCCCAGACGGGCCACCACACTTACAGCCCTCTGCATCGTCGCCTGCAACGAGTGCAGACG-T is Pathogenic according to our data. Variant chr3-49422364-TGCGCAACTAAGTGGACGACACAAGGCCGGGGGGAATGCCTGCAGGCGAAAGCCCAGACGGGCCACCACACTTACAGCCCTCTGCATCGTCGCCTGCAACGAGTGCAGACG-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 965232.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.-24_86del	p.Met1fs	frameshift_variant, start_lost	Exon 1 of 9	ENST00000273588.9	NP_000472.2
AMT	NM_000481.4	c.-24_86del		5_prime_UTR_truncation, exon_loss_variant	Exon 1 of 9	ENST00000273588.9	NP_000472.2
NICN1	NM_032316.3	c.*2359_*2468del		3_prime_UTR_variant	Exon 6 of 6	ENST00000273598.8	NP_115692.1
AMT	NM_000481.4	c.-24_86del		upstream_gene_variant		ENST00000273588.9	NP_000472.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AMT	ENST00000273588.9	c.-24_86del	p.Met1fs	frameshift_variant, start_lost	Exon 1 of 9	1	NM_000481.4	ENSP00000273588.3
AMT	ENST00000273588.9	c.-24_86del		5_prime_UTR_truncation, exon_loss_variant	Exon 1 of 9	1	NM_000481.4	ENSP00000273588.3
NICN1	ENST00000273598	c.*2359_*2468del		3_prime_UTR_variant	Exon 6 of 6	1	NM_032316.3	ENSP00000273598.4
ENSG00000283189	ENST00000636166.1	c.496-902_496-793del		intron_variant	Intron 4 of 10	5		ENSP00000490106.1
AMT	ENST00000273588.9	c.-24_86del		upstream_gene_variant		1	NM_000481.4	ENSP00000273588.3

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:1

Revision: criteria provided, single submitter

Submissions by phenotype

Glycine encephalopathy Pathogenic:1

Nov 03, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. If the downstream in-frame methionine at codon 49 is utilized for translation initiation, this variant would expect to disrupt the p.Gly47 amino acid residue in AMT. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8005589, 27362913, 23352163). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. This variant has not been reported in the literature in individuals with AMT-related conditions. ClinVar contains an entry for this variant (Variation ID: 965232). This variant is not present in population databases (ExAC no frequency). This sequence change affects the initiator methionine of the AMT mRNA. The next in-frame methionine is located at codon p.Met49. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs2049123051; hg19: chr3-49459797;