22-37974143-C-T
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Variant summary
Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_ModerateBP6BP7BS1BS2
The ENST00000396884.8(SOX10):c.753G>A(p.Ser251=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000398 in 1,611,248 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). Synonymous variant affecting the same amino acid position (i.e. S251S) has been classified as Likely benign.
Frequency
Genomes: 𝑓 0.00034 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00040 ( 0 hom. )
Consequence
SOX10
ENST00000396884.8 synonymous
ENST00000396884.8 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -0.272
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 -12 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.39).
BP6
Variant 22-37974143-C-T is Benign according to our data. Variant chr22-37974143-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 341617.We mark this variant Likely_benign, oryginal submissions are: {Benign=3, Uncertain_significance=1, Likely_benign=3}.
BP7
Synonymous conserved (PhyloP=-0.272 with no splicing effect.
BS1
Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000335 (51/152024) while in subpopulation EAS AF= 0.00193 (10/5174). AF 95% confidence interval is 0.00105. There are 0 homozygotes in gnomad4. There are 26 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High AC in GnomAd4 at 51 AD gene.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| SOX10 | NM_006941.4 | c.753G>A | p.Ser251= | synonymous_variant | 4/4 | ENST00000396884.8 | NP_008872.1 | |
| POLR2F | NM_001301130.2 | c.293+6973C>T | intron_variant | NP_001288059.1 | ||||
| POLR2F | NM_001301131.2 | c.293+6973C>T | intron_variant | NP_001288060.1 | ||||
| POLR2F | NM_001363825.1 | c.*38+1833C>T | intron_variant | NP_001350754.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| SOX10 | ENST00000396884.8 | c.753G>A | p.Ser251= | synonymous_variant | 4/4 | 1 | NM_006941.4 | ENSP00000380093 | P1 |
Frequencies
GnomAD3 genomes 0.000335 AC: 51AN: 152024Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000557 AC: 137AN: 246080Hom.: 0 AF XY: 0.000546 AC XY: 73AN XY: 133678
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GnomAD4 exome AF: 0.000404 AC: 590AN: 1459224Hom.: 0 Cov.: 40 AF XY: 0.000419 AC XY: 304AN XY: 726084
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GnomAD4 genome 0.000335 AC: 51AN: 152024Hom.: 0 Cov.: 32 AF XY: 0.000350 AC XY: 26AN XY: 74274
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:6
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:1Benign:3
| Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jul 21, 2017 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jan 01, 2023 | SOX10: BP4, BP7 - |
| Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 07, 2023 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Jul 28, 2020 | - - |
not specified Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Mar 20, 2017 | p.Ser251Ser 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. This variant has been identified in 0.1% (13 /10124) of Ashkenazi Jewish chromosomes and 0.3% (59/18832) of East Asian chromo somes by the Genome Aggregation Database (gnomAD, http://gnomAD.broadinstitute.o rg; dbSNP rs376907937). - |
PCWH syndrome Benign:1
| Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 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 12, 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