NM_138927.4:c.4640delA

Variant names:

• chr21-33553870-CA-C
• rs886039776
• NM_138927.4:c.4640delA

Variant summary

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

The NM_138927.4(SON):​c.4640delA​(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 rank	MANE	Protein	UniProt
SON	NM_138927.4	c.4640delA	p.His1547LeufsTer76	frameshift_variant	Exon 3 of 12	ENST00000356577.10	NP_620305.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SON	ENST00000356577.10	c.4640delA	p.His1547LeufsTer76	frameshift_variant	Exon 3 of 12	1	NM_138927.4	ENSP00000348984.4

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

Nov 02, 2016

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Sep 01, 2016

University of Washington Center for Mendelian Genomics, University of Washington

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

not provided Pathogenic:1

Jul 19, 2018

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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;