3-49422364-TGCGCAACTAAGTGGACGACACAAGGCCGGGGGGAATGCCTGCAGGCGAAAGCCCAGACGGGCCACCACACTTACAGCCCTCTGCATCGTCGCCTGCAACGAGTGCAGACG-T

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. 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. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. 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
• 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]

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

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• 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 VariationId is 965232.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000481.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AMT	NM_000481.4	MANE Select	c.-24_86del	p.Met1fs	frameshift start_lost	Exon 1 of 9	NP_000472.2
	AMT	NM_000481.4	MANE Select	c.-24_86del		5_prime_UTR_truncation exon_loss	Exon 1 of 9	NP_000472.2
	NICN1	NM_032316.3	MANE Select	c.*2359_*2468del		3_prime_UTR	Exon 6 of 6	NP_115692.1	Q9BSH3-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AMT	ENST00000273588.9	TSL:1 MANE Select	c.-24_86del	p.Met1fs	frameshift start_lost	Exon 1 of 9	ENSP00000273588.3	P48728-1
	AMT	ENST00000395338.7	TSL:1	c.-24_86del	p.Met1fs	frameshift start_lost	Exon 1 of 10	ENSP00000378747.2	P48728-4
	AMT	ENST00000273588.9	TSL:1 MANE Select	c.-24_86del		5_prime_UTR_truncation exon_loss	Exon 1 of 9	ENSP00000273588.3	P48728-1

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

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Glycine encephalopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.4

Splicing

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

Other links and lift over

dbSNP: rs2049123051; hg19: chr3-49459797;