NM_138927.4:c.5753_5756delTTAG

Variant names:

• chr21-33554981-CAGTT-C
• rs886039773
• NM_138927.4:c.5753_5756delTTAG

Variant summary

Our verdict is Pathogenic. The variant received 22 ACMG points: 22P and 0B. PVS1 PS3 PM2 PP5_Very_Strong

The NM_138927.4(SON):​c.5753_5756delTTAG​(p.Val1918GlufsTer87) 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 Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000741182: Real-time qPCR showed significantly decreased levels of SON mRNA transcripts in peripheral blood from two individuals harboring this variant, as compared to unaffected individuals negative for the variant (Kim, 2016).". Synonymous variant affecting the same amino acid position (i.e. V1918V) has been classified as Benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SON NM_138927.4 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:27 O:1
• Conservation: PhyloP100: 3.37
• Publications: 5 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: Labcorp Genetics (formerly Invitae), Orphanet, G2P, ClinGen, Illumina, PanelApp Australia

ACMG classification

Our verdict: Pathogenic. The variant received 22 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV000741182: Real-time qPCR showed significantly decreased levels of SON mRNA transcripts in peripheral blood from two individuals harboring this variant, as compared to unaffected individuals negative for the variant (Kim, 2016).
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 21-33554981-CAGTT-C is Pathogenic according to our data. Variant chr21-33554981-CAGTT-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 252929.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SON	NM_138927.4	MANE Select	c.5753_5756delTTAG	p.Val1918GlufsTer87	frameshift	Exon 3 of 12	NP_620305.3	P18583-1
	SON	NM_032195.3		c.5753_5756delTTAG	p.Val1918GlufsTer87	frameshift	Exon 3 of 7	NP_115571.3	P18583-3
	SON	NM_001291411.2		c.5753_5756delTTAG	p.Val1918GlufsTer87	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.5753_5756delTTAG	p.Val1918GlufsTer87	frameshift	Exon 3 of 12	ENSP00000348984.4	P18583-1
	SON	ENST00000300278.8	TSL:1	c.5753_5756delTTAG	p.Val1918GlufsTer87	frameshift	Exon 3 of 7	ENSP00000300278.2	P18583-3
	SON	ENST00000381692.6	TSL:1	c.245-2172_245-2169delTTAG		intron	N/A	ENSP00000371111.2	J3QSZ5

Frequencies

GnomAD3 genomes Cov.: 32

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

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
17	-	-	ZTTK syndrome (18)
5	-	-	not provided (5)
1	-	-	Global developmental delay;C2315100:Failure to thrive (1)
1	-	-	Hereditary spastic paraplegia 17 (1)
1	-	-	Inborn genetic diseases (1)
1	-	-	Neurodevelopmental abnormality (1)
1	-	-	See cases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.4
Mutation Taster		=3/197	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs886039773; hg19: chr21-34927287; COSMIC: COSV51659784; COSMIC: COSV51659784;