rs1382415023

chr21-33554944-AAAAG-A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_138927.4(SON):c.5717_5720del(p.Arg1906LysfsTer99) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SON NM_138927.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 3.52

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 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 21-33554944-AAAAG-A is Pathogenic according to our data. Variant chr21-33554944-AAAAG-A is described in ClinVar as [Pathogenic]. Clinvar id is 503761.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SON	NM_138927.4	c.5717_5720del	p.Arg1906LysfsTer99	frameshift_variant	3/12	ENST00000356577.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SON	ENST00000356577.10	c.5717_5720del	p.Arg1906LysfsTer99	frameshift_variant	3/12	1	NM_138927.4	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1461774 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 727194

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

ZTTK syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Centogene AG - the Rare Disease Company

Jul 16, 2019

- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 19, 2016

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Dec 21, 2017

The c.5717_5720delGAAA variant in the SON gene has been reported previously as a de novo alteration in a patient with multiple congenital anomalies, however, detailed clinical information was not provided (Farwell Hagman et al., 2017). The c.5717_5720delGAAA variant causes a frameshift starting with codon Arginine 1906, changes this amino acid to a Lysine residue, and creates a premature Stop codon at position 99 of the new reading frame, denoted p.Arg1906LysfsX99. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.5717_5720delGAAA variant is not observed in large population cohorts (Lek et al., 2016). We interpret c.5717_5720delGAAA 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: rs1382415023; hg19: chr21-34927250;