21-33543150-A-AGC

Variant names:

• chr21-33543150-A-AGC
• rs1555896735
• NM_138927.4:c.58_59insGC

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_138927.4(SON):​c.58_59insGC​(p.Ile20SerfsTer15) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: SON NM_138927.4 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 4.50
• 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]

GART (HGNC:4163): (phosphoribosylglycinamide formyltransferase, phosphoribosylglycinamide synthetase, phosphoribosylaminoimidazole synthetase) The protein encoded by this gene is a trifunctional polypeptide. It has phosphoribosylglycinamide formyltransferase, phosphoribosylglycinamide synthetase, phosphoribosylaminoimidazole synthetase activity which is required for de novo purine biosynthesis. This enzyme is highly conserved in vertebrates. Alternative splicing of this gene results in two transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 140 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 21-33543150-A-AGC is Pathogenic according to our data. Variant chr21-33543150-A-AGC is described in ClinVar as Pathogenic. ClinVar VariationId is 504070.Status of the report is criteria_provided_single_submitter, 1 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.58_59insGC	p.Ile20SerfsTer15	frameshift	Exon 1 of 12	NP_620305.3	P18583-1
	SON	NM_032195.3		c.58_59insGC	p.Ile20SerfsTer15	frameshift	Exon 1 of 7	NP_115571.3	P18583-3
	SON	NM_001291411.2		c.58_59insGC	p.Ile20SerfsTer15	frameshift	Exon 1 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.58_59insGC	p.Ile20SerfsTer15	frameshift	Exon 1 of 12	ENSP00000348984.4	P18583-1
	SON	ENST00000300278.8	TSL:1	c.58_59insGC	p.Ile20SerfsTer15	frameshift	Exon 1 of 7	ENSP00000300278.2	P18583-3
	SON	ENST00000381692.6	TSL:1	c.58_59insGC	p.Ile20SerfsTer15	frameshift	Exon 1 of 11	ENSP00000371111.2	J3QSZ5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.5
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: rs1555896735; hg19: chr21-34915456;