rs886039777

Positions:

• chr21-33549517-C-T

Variant summary

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

The ENST00000356577.10(SON):​c.286C>T​(p.Gln96Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SON ENST00000356577.10 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 2.87

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 21-33549517-C-T is Pathogenic according to our data. Variant chr21-33549517-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 252926.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-33549517-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SON	NM_138927.4	c.286C>T	p.Gln96Ter	stop_gained	3/12	ENST00000356577.10	NP_620305.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SON	ENST00000356577.10	c.286C>T	p.Gln96Ter	stop_gained	3/12	1	NM_138927.4	ENSP00000348984	P3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

ZTTK syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	May 02, 2023	The heterozygous p.Gln96Ter variant in SON was identified by our study in one individual with hypoplasia of the corpus callosum and global developmental delay. Trio exome analysis showed this variant to be de novo. The p.Gln96Ter has been previously reported in one individual with ZTTK syndrome (PMID: 27545676) and was found to be de novo in this individual with confirmed paternity and maternity. The number of reported affected individuals with this variant is slightly greater than expected compared to non-affected individuals with this variant. This variant has also been reported in ClinVar (Variation ID: 252926) and has been interpreted as pathogenic by OMIM and as likely pathogenic by Baylor Genetics. This variant was absent from large population studies. This nonsense variant leads to a premature termination codon at position 96, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the SON gene is an established disease mechanism in autosomal dominant ZTTK syndrome. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant ZTTK syndrome. ACMG/AMP Criteria applied: PVS1, PS2_Moderate, PS4_Supporting, PM2_Supporting (Richards 2015). -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 02, 2016	- -

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

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	36
DANN	Uncertain	1.0
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Uncertain	0.80	D
MutationTaster	Benign	1.0	A;A;A;A;D
Vest4		0.89
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs886039777; hg19: chr21-34921823;