rs886039776

Positions:

• chr21-33553870-CA-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_138927.4(SON):​c.4640del​(p.His1547LeufsTer76) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SON NM_138927.4 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: 0.555

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]

ACMG classification

Verdict is Pathogenic. Variant got 12 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 21-33553870-CA-C is Pathogenic according to our data. Variant chr21-33553870-CA-C is described in ClinVar as [Pathogenic]. Clinvar id is 265776.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr21-33553870-CA-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SON	NM_138927.4	c.4640del	p.His1547LeufsTer76	frameshift_variant	3/12	ENST00000356577.10	NP_620305.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SON	ENST00000356577.10	c.4640del	p.His1547LeufsTer76	frameshift_variant	3/12	1	NM_138927.4	ENSP00000348984	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 39

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

Submissions by phenotype

ZTTK syndrome Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 02, 2016	- -
Likely pathogenic, no assertion criteria provided	research	University of Washington Center for Mendelian Genomics, University of Washington	Sep 01, 2016	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jul 19, 2018

The c.4640delA variant in the SON gene has been reported previously using alternate nomenclature c.4640del in the apparently de novo state in association with a SON-related disorder (Kim et al., 2016). The c.4640delA variant causes a frameshift starting with codon Histidine 1547, changes this amino acid to a Leucine residue, and creates a premature Stop codon at position 76 of the new reading frame, denoted p.His1547LeufsX76. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.4640delA variant is not observed in large population cohorts (Lek et al., 2016). We interpret c.4640delA as a pathogenic variant. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs886039776; hg19: chr21-34926176;