rs797045825
Variant summary
Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1PM2PP2PP3_StrongPP5_Very_Strong
The NM_022455.5(NSD1):c.5990A>G(p.Tyr1997Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_022455.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 17 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 28
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Sotos syndrome Pathogenic:4
This sequence variant is a single nucleotide substitution (A>G) at position 5990 of the coding sequence of the NSD1 gene that results in a tyrosine to cysteine amino acid change at residue 1997 of the Nuclear Receptor-Binding SET Domain-Containing Protein 1. Variants in the NSD1 gene have been previously shown to be associated with Sotos syndrome, often de novo, but can be inherited (PMID: 12464997, 12525543). This is a previously reported variant (ClinVar 211738) and has been reported in individuals affected by an NSD1-related disorder (PMID: 21084978, 15942875). This variant is absent in the gnomAD v4.1.0 population database (0 in approximately 1,610,000 alleles). Multiple bioinformatic tools predict that this amino acid change would be damaging, and the Tyr1997 residue at this position is highly conserved across the vertebrate species examined. In vitro functional studies showed the p.Tyr1997Cys mutation results in reduced or abolished enzyme methylation activity (PMID:24412544). Haploinsufficiency in NSD1 is a known mechanism of disease (PMID:11896389 ). Based upon the evidence, we consider this variant to be pathogenic. ACMG Criteria: PM2, PP3, PS2, PS3 -
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In-silico prediction tools (REVEL, CADD) are consistent in predicting that the variant to be disease-causing and affect protein function. Monoallelic variants in ABCA1 gene are associated with HDL deficiency, familial 1 (MIM#604091). -
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Inborn genetic diseases Pathogenic:1
The p.Y1997C pathogenic mutation (also known as c.5990A>G), located in coding exon 18 of the NSD1 gene, results from an A to G substitution at nucleotide position 5990. The tyrosine at codon 1997 is replaced by cysteine, an amino acid with highly dissimilar properties. This mutation was first reported to be de novo in a patient with childhood overgrowth, dysmorphic facial features, and advanced bone age (Rio M et al. J. Med. Genet., 2003 Jun;40:436-40). It has subsequently been reported in multiple individuals with Sotos syndrome phenotypes (Tatton-Brown K et al. Am. J. Hum. Genet., 2005 Aug;77:193-204; Choufani S et al. Nat Commun, 2015 Dec;6:10207). Additionally, in vitro functional studies showed the p.Y1997C mutation results in reduced or abolished enzyme methylation activity (Kudithipudi S et al. Chem. Biol., 2014 Feb;21:226-37). Based on the supporting evidence, p.Y1997C is interpreted as a disease-causing mutation. -
not provided Pathogenic:1
For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt NSD1 protein function. ClinVar contains an entry for this variant (Variation ID: 211738). This variant is also known as 5989A/G, Y1996C. This missense change has been observed in individual(s) with clinical features of NSD1-related conditions (PMID: 12807965). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 1997 of the NSD1 protein (p.Tyr1997Cys). -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at