rs886039775

Variant names:

• chr21-33555232-T-TCC
• rs886039775
• NM_138927.4:c.6002_6003insCC

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_138927.4(SON):​c.6002_6003insCC​(p.Arg2002GlnfsTer5) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. S2001S) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 31)
• Consequence: SON NM_138927.4 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 4.06
• Publications: 3 publications found

Genes affected

SON (HGNC:11183): (SON DNA and RNA binding protein) This gene encodes a protein that contains multiple simple repeats. The encoded protein binds RNA and promotes pre-mRNA splicing, particularly of transcripts with poor splice sites. The protein also recognizes a specific DNA sequence found in the human hepatitis B virus (HBV) and represses HBV core promoter activity. There is a pseudogene for this gene on chromosome 1. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2013]

SON Gene-Disease associations (from GenCC):

• ZTTK syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Illumina, G2P, Orphanet, Labcorp Genetics (formerly Invitae), ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 21-33555232-T-TCC is Pathogenic according to our data. Variant chr21-33555232-T-TCC is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 265775.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_138927.4. 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
	SON	NM_138927.4	MANE Select	c.6002_6003insCC	p.Arg2002GlnfsTer5	frameshift	Exon 3 of 12	NP_620305.3
	SON	NM_032195.3		c.6002_6003insCC	p.Arg2002GlnfsTer5	frameshift	Exon 3 of 7	NP_115571.3
	SON	NM_001291411.2		c.6002_6003insCC	p.Arg2002GlnfsTer5	frameshift	Exon 3 of 5	NP_001278340.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SON	ENST00000356577.10	TSL:1 MANE Select	c.6002_6003insCC	p.Arg2002GlnfsTer5	frameshift	Exon 3 of 12	ENSP00000348984.4
	SON	ENST00000300278.8	TSL:1	c.6002_6003insCC	p.Arg2002GlnfsTer5	frameshift	Exon 3 of 7	ENSP00000300278.2
	SON	ENST00000421541.1	TSL:1	c.185_186insCC	p.Arg63GlnfsTer5	frameshift	Exon 1 of 5	ENSP00000405807.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic/Likely pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
2	-	-	ZTTK syndrome (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.1
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs886039775; hg19: chr21-34927538;