dbSNP rs886039774: SON:p.Arg1850IlefsTer3 (chr21-33554776-AAG-A) – ACMG Classification: Pathogenic (12 pts)

Variant summary

Our verdict is . The variant received 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_138927.4(SON):c.5549_5550delGA(p.Arg1850IlefsTer3) 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

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, single submitter P:3

Conservation

PhyloP100: 3.08

Publications

1 publications found

Variant links:

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: PanelApp Australia, Orphanet, ClinGen, Illumina, G2P, Labcorp Genetics (formerly Invitae)

SON links:

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new If you want to explore the variant's impact on the transcript NM_138927.4, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 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 21-33554776-AAG-A is Pathogenic according to our data. Variant chr21-33554776-AAG-A is described in ClinVar as Pathogenic. ClinVar VariationId is 265774.Status of the report is criteria_provided_single_submitter, 1 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SON	NM_138927.4	MANE Select	c.5549_5550delGA	p.Arg1850IlefsTer3	frameshift	Exon 3 of 12	NP_620305.3	P18583-1
SON	NM_032195.3		c.5549_5550delGA	p.Arg1850IlefsTer3	frameshift	Exon 3 of 7	NP_115571.3	P18583-3
SON	NM_001291411.2		c.5549_5550delGA	p.Arg1850IlefsTer3	frameshift	Exon 3 of 5	NP_001278340.2	P18583-6

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SON	ENST00000356577.10	TSL:1 MANE Select	c.5549_5550delGA	p.Arg1850IlefsTer3	frameshift	Exon 3 of 12	ENSP00000348984.4	P18583-1
SON	ENST00000300278.8	TSL:1	c.5549_5550delGA	p.Arg1850IlefsTer3	frameshift	Exon 3 of 7	ENSP00000300278.2	P18583-3
SON	ENST00000381692.6	TSL:1	c.245-2376_245-2375delGA		intron	N/A	ENSP00000371111.2	J3QSZ5

Frequencies

GnomAD3 genomes

Cov.:

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

ZTTK syndrome (2)

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

3.1

Mutation Taster

=1/199

disease causing (ClinVar)

(source)

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over