chr21-33552303-G-GA

Variant names:

• chr21-33552303-G-GA
• rs886039778
• NM_138927.4:c.3073dupA

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_138927.4(SON):​c.3073dupA​(p.Met1025AsnfsTer6) 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 (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 31)
• Consequence: SON NM_138927.4 frameshift
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 2.31
• Publications: 3 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: Illumina, G2P, Orphanet, Labcorp Genetics (formerly Invitae), ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 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 21-33552303-G-GA is Pathogenic according to our data. Variant chr21-33552303-G-GA is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 252927.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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SON	NM_138927.4	MANE Select	c.3073dupA	p.Met1025AsnfsTer6	frameshift	Exon 3 of 12	NP_620305.3
	SON	NM_032195.3		c.3073dupA	p.Met1025AsnfsTer6	frameshift	Exon 3 of 7	NP_115571.3
	SON	NM_001291411.2		c.3073dupA	p.Met1025AsnfsTer6	frameshift	Exon 3 of 5	NP_001278340.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SON	ENST00000356577.10	TSL:1 MANE Select	c.3073dupA	p.Met1025AsnfsTer6	frameshift	Exon 3 of 12	ENSP00000348984.4
	SON	ENST00000300278.8	TSL:1	c.3073dupA	p.Met1025AsnfsTer6	frameshift	Exon 3 of 7	ENSP00000300278.2
	SON	ENST00000381692.6	TSL:1	c.245-4852dupA		intron	N/A	ENSP00000371111.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 41

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions as Germline

Significance: Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	ZTTK syndrome (2)
1	-	-	Global developmental delay;C2315100:Failure to thrive (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.3
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs886039778; hg19: chr21-34924609;