rs1555899177

Variant names:

• chr21-33554004-AACTC-A
• rs1555899177
• NM_138927.4:c.4774_4777delACTC

GermlineCancer (beta)

Variant summary

Our verdict is Pathogenic.

+12 Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 12 classification points (ACMG Germline Pathogenicity v2019). 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
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 0.831
• Publications: 0 publications found

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

Classification according to ACMG Germline Pathogenicity v2019

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. A new stop codon is introduced in the shifted frame, truncating the protein to ~1620 amino acids (806 amino acids lost).
• 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

Sel.	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

Sel.	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

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 2 sources Large-scale international reference populations
GnomAD3 genomes					32
GnomAD4 genome					32

Showing 2 sources

Tested, but no data found:GnomAD4 exomeIf GnomAD4 is missing, the position is probably not covered by the project.

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Inborn genetic diseases (1)

Computational Scores

Algorithm	Calibrated prediction	Prediction	Score
Mutation Taster	N/A	disease causing (ClinVar)	1/199
PhyloP100	Benign	-	0.83

Showing 2 of 2 scores

Other links and lift over

dbSNP: rs1555899177;

hg19: chr21-34926310;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar