chr21-33554004-AACTC-A

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

Classification was made for transcript:

Our verdict: Pathogenic. The variant received 12 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PVS1Null variant in LOF gene		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).
	PM2Absent/extremely low in population databases		Absent from gnomAD (AD/XL gene) — PM2; Absent from gnomAD at well-covered site (MOI: AD/XL) (threshold 0.0001) — PM2 moderate.
	PP5Reputable source reports pathogenic		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	Prot: NP_620305.3 UniProt:
	SON NM_032195.3		c.4774_4777delACTC p.Thr1592TyrfsTer30	frameshift	Exon 3 of 7	Prot: NP_115571.3 UniProt:
	SON NM_001291411.2		c.4774_4777delACTC p.Thr1592TyrfsTer30	frameshift	Exon 3 of 5	Prot: NP_001278340.2 UniProt:

SON NM_138927.4

MANE Select

HGVSc / HGVSpc.4774_4777delACTCp.Thr1592TyrfsTer30

Exon rankExon 3 of 12

frameshift

Prot: NP_620305.3UniProt: P18583-1

SON NM_032195.3

HGVSc / HGVSpc.4774_4777delACTCp.Thr1592TyrfsTer30

Exon rankExon 3 of 7

frameshift

Prot: NP_115571.3UniProt: P18583-3

SON NM_001291411.2

HGVSc / HGVSpc.4774_4777delACTCp.Thr1592TyrfsTer30

Exon rankExon 3 of 5

frameshift

Prot: NP_001278340.2UniProt: P18583-6

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	SON ENST00000356577.10	TSL:1MANE Select	c.4774_4777delACTC p.Thr1592TyrfsTer30	frameshift	Exon 3 of 12	Prot: ENSP00000348984.4 UniProt:
	SON ENST00000300278.8	TSL:1	c.4774_4777delACTC p.Thr1592TyrfsTer30	frameshift	Exon 3 of 7	Prot: ENSP00000300278.2 UniProt:
	SON ENST00000381692.6	TSL:1	c.245-3151_245-3148delACTC	intron	Intron 2 of 10	Prot: ENSP00000371111.2 UniProt:

SON ENST00000356577.10

TSL:1MANE Select

HGVSc / HGVSpc.4774_4777delACTCp.Thr1592TyrfsTer30

Exon rankExon 3 of 12

frameshift

Prot: ENSP00000348984.4UniProt: P18583-1

SON ENST00000300278.8

TSL:1

HGVSc / HGVSpc.4774_4777delACTCp.Thr1592TyrfsTer30

Exon rankExon 3 of 7

frameshift

Prot: ENSP00000300278.2UniProt: P18583-3

SON ENST00000381692.6

TSL:1

HGVSc / HGVSpc.245-3151_245-3148delACTC

Exon rankIntron 2 of 10

intron

Prot: ENSP00000371111.2UniProt: 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	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32

Showing 2 sources

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

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

Computational Scores

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

Showing 2 of 2 scores

Splicing Scores

No splicing scores have been computed for this variant.

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.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs1555899177;

hg19: chr21-34926310;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar