rs375051877
Variant summary
Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP2BP4_StrongBP6_Very_StrongBS2
The NM_022455.5(NSD1):āc.1477C>Gā(p.Pro493Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000186 in 1,613,996 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (ā ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P493L) has been classified as Likely benign.
Frequency
Consequence
NM_022455.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -15 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NSD1 | NM_022455.5 | c.1477C>G | p.Pro493Ala | missense_variant | 5/23 | ENST00000439151.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NSD1 | ENST00000439151.7 | c.1477C>G | p.Pro493Ala | missense_variant | 5/23 | 1 | NM_022455.5 | P2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000855 AC: 13AN: 152120Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000358 AC: 9AN: 251094Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135706
GnomAD4 exome AF: 0.0000116 AC: 17AN: 1461876Hom.: 0 Cov.: 35 AF XY: 0.00000825 AC XY: 6AN XY: 727236
GnomAD4 genome ? AF: 0.0000855 AC: 13AN: 152120Hom.: 0 Cov.: 31 AF XY: 0.0000942 AC XY: 7AN XY: 74300
ClinVar
Submissions by phenotype
Sotos syndrome Benign:2
Benign, criteria provided, single submitter | clinical testing | Invitae | Sep 15, 2022 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jul 15, 2021 | - - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 03, 2023 | Variant summary: NSD1 c.1477C>G (p.Pro493Ala) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 5e-05 in 282496 control chromosomes (i.e. 14 heterozygotes) in gnomAD v2.1. The relatively high number of carriers suggests a benign role for this variant for an early onset, high penetrance dominant disease phenotype. To our knowledge, no occurrence of c.1477C>G in individuals affected with Sotos Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as likely benign. - |
not provided Benign:1
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Nov 08, 2019 | - - |
NSD1-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Nov 14, 2023 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at