rs753743263

Positions:

• chr3-49422508-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP5 BP4

The ENST00000395338.7(AMT):​c.-58C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000072 in 1,388,010 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: AMT ENST00000395338.7 5_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2
• Conservation: PhyloP100: 3.03

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-49422508-G-A is Pathogenic according to our data. Variant chr3-49422508-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 555489.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Uncertain_significance=2}. Variant chr3-49422508-G-A is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.23). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NICN1	NM_032316.3	c.*2325C>T		3_prime_UTR_variant	6/6	ENST00000273598.8
AMT	NM_000481.4			upstream_gene_variant		ENST00000273588.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NICN1	ENST00000273598.8	c.*2325C>T		3_prime_UTR_variant	6/6	1	NM_032316.3	P1
AMT	ENST00000273588.9			upstream_gene_variant		1	NM_000481.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000502 AC: 1 AN: 199220 Hom.: 0 AF XY: 0.00000921 AC XY: 1 AN XY: 108570

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000120

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.20e-7 AC: 1 AN: 1388010 Hom.: 0 Cov.: 23 AF XY: 0.00000145 AC XY: 1 AN XY: 691738

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.48e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Non-ketotic hyperglycinemia Pathogenic:1 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jul 28, 2023	This variant occurs in a non-coding region of the AMT gene. It does not change the encoded amino acid sequence of the AMT protein. This variant is present in population databases (rs753743263, gnomAD 0.001%). This variant has been observed in individual(s) with glycine encephalopathy (PMID: 27362913; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 555489). For these reasons, this variant has been classified as Pathogenic. -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Dec 06, 2017	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Oct 11, 2023

Variant summary: AMT c.-58C>T is located in the untranscribed region upstream of the AMT gene region. The variant allele was found at a frequency of 5e-06 in 199220 control chromosomes (gnomAD). c.-58C>T has been reported in the literature in three alleles from individuals affected with Glycine Encephalopathy (Non-Ketotic Hyperglycinemia), including at least one case where it was found in trans with a pathogenic variant (Coughlin_2017); however, the remaining two alleles were reported as an uninformative genotype (i.e. zygosity not specified). These data do not allow any strong conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Yet it has been noted that several 5'UTR variants located within nucleotides c.-55 to c.-66 were observed in affected individuals from the Coughlin_2017 study cohort, suggesting this could represent a regulatory region for the AMT gene. The following publication has been ascertained in the context of this evaluation (PMID: 27362913). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. One submitter, also citing internal data, classified the variant as pathogenic, and one submitter classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic until further clinical and/or functional data becomes available. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.23
CADD	Uncertain	24
DANN	Benign	0.94

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: rs753743263; hg19: chr3-49459941; COSMIC: COSV99864325; COSMIC: COSV99864325;