rs147334218
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Variant summary
Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2
The NM_006941.4(SOX10):c.822C>T(p.Gly274=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00155 in 1,614,022 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.0015 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0016 ( 3 hom. )
Consequence
SOX10
NM_006941.4 synonymous
NM_006941.4 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: 1.02
Genes affected
SOX10 (HGNC:11190): (SRY-box transcription factor 10) This gene encodes a member of the SOX (SRY-related HMG-box) family of transcription factors involved in the regulation of embryonic development and in the determination of the cell fate. The encoded protein may act as a transcriptional activator after forming a protein complex with other proteins. This protein acts as a nucleocytoplasmic shuttle protein and is important for neural crest and peripheral nervous system development. Mutations in this gene are associated with Waardenburg-Shah and Waardenburg-Hirschsprung disease. [provided by RefSeq, Jul 2008]
POLR2F (HGNC:9193): (RNA polymerase II, I and III subunit F) This gene encodes the sixth largest subunit of RNA polymerase II, the polymerase responsible for synthesizing messenger RNA in eukaryotes. In yeast, this polymerase subunit, in combination with at least two other subunits, forms a structure that stabilizes the transcribing polymerase on the DNA template. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2014]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -21 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.52).
BP6
Variant 22-37974074-G-A is Benign according to our data. Variant chr22-37974074-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 227960.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-37974074-G-A is described in Lovd as [Likely_benign].
BP7
Synonymous conserved (PhyloP=1.02 with no splicing effect.
BS1
Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00149 (227/152322) while in subpopulation AMR AF= 0.00327 (50/15296). AF 95% confidence interval is 0.00255. There are 0 homozygotes in gnomad4. There are 109 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High AC in GnomAd4 at 227 AD gene.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| SOX10 | NM_006941.4 | c.822C>T | p.Gly274= | synonymous_variant | 4/4 | ENST00000396884.8 | NP_008872.1 | |
| POLR2F | NM_001301130.2 | c.293+6904G>A | intron_variant | NP_001288059.1 | ||||
| POLR2F | NM_001301131.2 | c.293+6904G>A | intron_variant | NP_001288060.1 | ||||
| POLR2F | NM_001363825.1 | c.*38+1764G>A | intron_variant | NP_001350754.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| SOX10 | ENST00000396884.8 | c.822C>T | p.Gly274= | synonymous_variant | 4/4 | 1 | NM_006941.4 | ENSP00000380093 | P1 |
Frequencies
GnomAD3 genomes 0.00150 AC: 228AN: 152204Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00112 AC: 280AN: 249214Hom.: 0 AF XY: 0.00110 AC XY: 148AN XY: 134894
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GnomAD4 exome AF: 0.00156 AC: 2277AN: 1461700Hom.: 3 Cov.: 40 AF XY: 0.00155 AC XY: 1130AN XY: 727178
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GnomAD4 genome 0.00149 AC: 227AN: 152322Hom.: 0 Cov.: 32 AF XY: 0.00146 AC XY: 109AN XY: 74482
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:10
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Benign:5
| Benign, criteria provided, single submitter | clinical testing | GeneDx | Jun 25, 2018 | This variant is associated with the following publications: (PMID: 20444197, 20130826, 11499640) - |
| Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
| Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | May 01, 2024 | SOX10: BP4, BP7 - |
| Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 25, 2024 | - - |
| Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
not specified Benign:2
| Likely benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Oct 26, 2017 | p.Gly274Gly in exon 4 of SOX10: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue and is not located wi thin the splice consensus sequence. It has been identified in 0.17% (211/124588) of European chromosomes and 0.21% (73/34420) of Latino chromosomes by the Genom e Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs147334 218). ACMG/AMP Criteria applied: BP4, BP7, BS1_P (Richards 2015). - |
| Likely benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | May 01, 2017 | - - |
SOX10-related disorder Benign:1
| Likely benign, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Jan 29, 2020 | 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). - |
PCWH syndrome Benign:1
| Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
Waardenburg syndrome Benign:1
| Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
Computational scores
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Name
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at