Genetic Variant SON:p.Thr1592TyrfsTer30 (chr21-33554004-AACTC-A) – ACMG Classification: Pathogenic (12 pts)

Variant summary

Our verdict is . The variant received 12 classification points (ACMG Germline Pathogenicity v2019): 12P and 0B. PVS1PM2PP5_Moderate

The NM_138927.4(SON):c.4774_4777delACTC (p.Thr1592TyrfsTer30) variant causes a frameshift change. The variant is predicted to lead to nonsense-mediated mRNA decay (NMD). Note: allele frequency estimates from gnomAD may be inaccurate for this variant type (MNP or indel longer than 3 bp) due to technology limitations. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (★).

Frequency

Genomes: not found (cov: 32)

Consequence

SON
NM_138927.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 0.831

Publications

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

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.

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript

Our verdict: Pathogenic. The variant received 12 points.

PVS1

Frameshift/stop-gained, NMD predicted, LoF disease mechanism — very strong (PVS1); Frameshift (exon 3 of 12) at amino acid 1592 of 2426, predicted to trigger nonsense-mediated mRNA decay. Loss of function is a known disease mechanism for this gene. No in-frame stop codon was found in the shifted reading frame.

PM2

Absent from gnomAD (AD/XL gene) — PM2; Absent from gnomAD at well-covered site (MOI: AD/XL) (threshold 0.0001) — PM2 moderate.

PP5

ClinVar 1-star pathogenic — moderate (PP5); ClinVar germline classification: Pathogenic/Likely Pathogenic, 1 star(s).

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_138927.4. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SON	NM_138927.4	MANE Select	c.4774_4777delACTC	p.Thr1592TyrfsTer30	frameshift	Exon 3 of 12	NP_620305.3	P18583-1
SON	NM_032195.3		c.4774_4777delACTC	p.Thr1592TyrfsTer30	frameshift	Exon 3 of 7	NP_115571.3	P18583-3
SON	NM_001291411.2		c.4774_4777delACTC	p.Thr1592TyrfsTer30	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.4774_4777delACTC	p.Thr1592TyrfsTer30	frameshift	Exon 3 of 12	ENSP00000348984.4	P18583-1
SON	ENST00000300278.8	TSL:1	c.4774_4777delACTC	p.Thr1592TyrfsTer30	frameshift	Exon 3 of 7	ENSP00000300278.2	P18583-3
SON	ENST00000381692.6	TSL:1	c.245-3151_245-3148delACTC		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

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.83

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

Classification according to ACMG Germline Pathogenicity v2019

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over