rs1114167303

Positions:

• chr21-33553078-TGTATG-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_138927.4(SON):​c.3852_3856del​(p.Met1284IlefsTer2) 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 Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. C1283C) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SON NM_138927.4 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 2.24

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 18 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 21-33553078-TGTATG-T is Pathogenic according to our data. Variant chr21-33553078-TGTATG-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 252928.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-33553078-TGTATG-T is described in Lovd as [Pathogenic]. Variant chr21-33553078-TGTATG-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SON	NM_138927.4	c.3852_3856del	p.Met1284IlefsTer2	frameshift_variant	3/12	ENST00000356577.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SON	ENST00000356577.10	c.3852_3856del	p.Met1284IlefsTer2	frameshift_variant	3/12	1	NM_138927.4	P3

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

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

ZTTK syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	May 21, 2020	A heterozygous variant was identified, NM_138927.2(SON):c.3852_3856del in exon 3 of 12 of the SON gene (NB: This variant is non-coding in an alternative transcript). This deletion is predicted to cause a frameshift from amino acid position 1284 introducing a stop codon 2 residues downstream, NP_620305.2(SON):p.(Met1284Ilefs*2). The variant is predicted to result in loss of protein function through nonsense-mediated decay, which is a reported mechanism of pathogenicity for this gene. This variant is not present in the gnomAD population database. It has previously been reported as pathogenic in clinical cases, and was also shown to be de novo (ClinVar, Tokita, M., et al. (2016), Kim, J., et al. (2016)). Multiple variants predicted to cause NMD have also been reported as pathogenic (ClinVar). Based on information available at the time of curation, this variant has been classified as PATHOGENIC. -
Likely pathogenic, no assertion criteria provided	research	University of Washington Center for Mendelian Genomics, University of Washington	Sep 01, 2016	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 20, 2022	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 34521999, 28191890, 28135719, 27545676, 27545680, 31785789) -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Apr 02, 2021	For these reasons, this variant has been classified as Pathogenic. This variant has been observed in individuals with clinical features of SON-related conditions (PMID: 27545676, 27545680, 28135719). ClinVar contains an entry for this variant (Variation ID: 252928). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Met1284Ilefs*2) in the SON gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SON are known to be pathogenic (PMID: 27545676, 27545680). -

Global developmental delay;C2315100:Failure to thrive Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Jun 21, 2016

- -

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: rs1114167303; hg19: chr21-34925384;