rs1555939381

Variant names:

• chr22-37983313-CCGAAGCTAGAGGGCCCGAGCCCGGGGGGCGGTCGGGTGCTCACCTCCAGAGCTTGCCCAGCGTCTTGCTGAGCTCAGCGTTGTGCAGGTGCGGGTACTGGTCCGCGAGCTTCCTGCGCGCTGCCTGAGCCCACACCATGAAGGCGTTCATGGGCCGCTTGACGTGCGGCTTGCTTTTGCTGGCGCCGTTGACGCGCACGGGCATGGGCACCAGCGTCCAGTCGTAGCCGCTGAGCACCTGGCTGACGGCCTCG-C
• rs1555939381
• NM_006941.4:c.219_428+43del

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PVS1 PP5

The ENST00000396884.8(SOX10):​c.219_428+43del​(p.Glu74_Arg143del) variant causes a splice donor, disruptive inframe deletion, splice region, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SOX10 ENST00000396884.8 splice_donor, disruptive_inframe_deletion, splice_region, intron
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 2.68
• Publications: 1 publications found

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]

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PP5: Variant 22-37983313-CCGAAGCTAGAGGGCCCGAGCCCGGGGGGCGGTCGGGTGCTCACCTCCAGAGCTTGCCCAGCGTCTTGCTGAGCTCAGCGTTGTGCAGGTGCGGGTACTGGTCCGCGAGCTTCCTGCGCGCTGCCTGAGCCCACACCATGAAGGCGTTCATGGGCCGCTTGACGTGCGGCTTGCTTTTGCTGGCGCCGTTGACGCGCACGGGCATGGGCACCAGCGTCCAGTCGTAGCCGCTGAGCACCTGGCTGACGGCCTCG-C is Pathogenic according to our data. Variant chr22-37983313-CCGAAGCTAGAGGGCCCGAGCCCGGGGGGCGGTCGGGTGCTCACCTCCAGAGCTTGCCCAGCGTCTTGCTGAGCTCAGCGTTGTGCAGGTGCGGGTACTGGTCCGCGAGCTTCCTGCGCGCTGCCTGAGCCCACACCATGAAGGCGTTCATGGGCCGCTTGACGTGCGGCTTGCTTTTGCTGGCGCCGTTGACGCGCACGGGCATGGGCACCAGCGTCCAGTCGTAGCCGCTGAGCACCTGGCTGACGGCCTCG-C is described in ClinVar as Pathogenic. ClinVar VariationId is 7405.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000396884.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SOX10	NM_006941.4	MANE Select	c.219_428+43del	p.Glu74_Arg143del	splice_donor disruptive_inframe_deletion splice_region intron	Exon 2 of 4	NP_008872.1
	POLR2F	NM_001301130.2		c.294-2838_294-2586del		intron	N/A	NP_001288059.1
	POLR2F	NM_001363825.1		c.*38+11006_*38+11258del		intron	N/A	NP_001350754.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SOX10	ENST00000396884.8	TSL:1 MANE Select	c.219_428+43del	p.Glu74_Arg143del	splice_donor disruptive_inframe_deletion splice_region intron	Exon 2 of 4	ENSP00000380093.2
	SOX10	ENST00000360880.6	TSL:1	c.219_428+43del	p.Glu74_Arg143del	splice_donor disruptive_inframe_deletion splice_region intron	Exon 3 of 5	ENSP00000354130.2
	SOX10	ENST00000446929.5	TSL:2	c.-154_56+43del		exon_loss splice_region	Exon 1 of 4	ENSP00000399777.1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Waardenburg syndrome type 2E, without neurologic involvement (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.7
Mutation Taster		=1/199	disease causing (ClinVar)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1555939381; hg19: chr22-38379320;