21-33546193-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_138927.4(SON):c.78-20C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.021 in 1,576,156 control chromosomes in the GnomAD database, including 387 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.016 (25 hom., cov: 33)
  • Exomes 𝑓: 0.022 (362 hom.)
• Consequence: SON NM_138927.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.08

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 21-33546193-C-T is Benign according to our data. Variant chr21-33546193-C-T is described in ClinVar as [Benign]. Clinvar id is 1603796.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0155 (2362/152068) while in subpopulation NFE AF= 0.0232 (1575/67988). AF 95% confidence interval is 0.0222. There are 25 homozygotes in gnomad4. There are 1124 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 2360 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SON	NM_138927.4	c.78-20C>T		intron_variant		ENST00000356577.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SON	ENST00000356577.10	c.78-20C>T		intron_variant		1	NM_138927.4	P3

Frequencies

GnomAD3 genomes AF: 0.0155 AC: 2360 AN: 151950 Hom.: 25 Cov.: 33

Gnomad AFR AF: 0.00438

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0155

Gnomad ASJ AF: 0.0182

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00580

Gnomad FIN AF: 0.0227

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0232

Gnomad OTH AF: 0.0154

GnomAD3 exomes AF: 0.0170 AC: 3831 AN: 225556 Hom.: 48 AF XY: 0.0172 AC XY: 2112 AN XY: 122842

Gnomad AFR exome AF: 0.00444

Gnomad AMR exome AF: 0.00731

Gnomad ASJ exome AF: 0.0182

Gnomad EAS exome AF: 0.0000603

Gnomad SAS exome AF: 0.00749

Gnomad FIN exome AF: 0.0278

Gnomad NFE exome AF: 0.0236

Gnomad OTH exome AF: 0.0215

GnomAD4 exome AF: 0.0216 AC: 30732 AN: 1424088 Hom.: 362 Cov.: 29 AF XY: 0.0213 AC XY: 15056 AN XY: 707646

Gnomad4 AFR exome AF: 0.00258

Gnomad4 AMR exome AF: 0.00797

Gnomad4 ASJ exome AF: 0.0182

Gnomad4 EAS exome AF: 0.0000510

Gnomad4 SAS exome AF: 0.00717

Gnomad4 FIN exome AF: 0.0281

Gnomad4 NFE exome AF: 0.0243

Gnomad4 OTH exome AF: 0.0198

GnomAD4 genome AF: 0.0155 AC: 2362 AN: 152068 Hom.: 25 Cov.: 33 AF XY: 0.0151 AC XY: 1124 AN XY: 74330

Gnomad4 AFR AF: 0.00436

Gnomad4 AMR AF: 0.0155

Gnomad4 ASJ AF: 0.0182

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00601

Gnomad4 FIN AF: 0.0227

Gnomad4 NFE AF: 0.0232

Gnomad4 OTH AF: 0.0152

Alfa AF: 0.0192 Hom.: 7

Bravo AF: 0.0150

Asia WGS AF: 0.00347 AC: 12 AN: 3474

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
Cadd	Benign	14
Dann	Benign	0.62
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs74772689; hg19: chr21-34918499;