21-33559604-A-G

Variant names:

• chr21-33559604-A-G
• rs767907159
• NM_138927.4:c.6486A>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Moderate BP6_Moderate BP7 BS1 BS2

The NM_138927.4(SON):​c.6486A>G​(p.Pro2162Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000302 in 1,458,110 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000030 (0 hom.)
• Consequence: SON NM_138927.4 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.646
• 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]

DONSON (HGNC:2993): (DNA replication fork stabilization factor DONSON) This gene lies downstream of the SON gene and spans 10 kb on chromosome 21. The function of this gene is unknown. [provided by RefSeq, Jul 2008]

DONSON Gene-Disease associations (from GenCC):

• microcephaly, short stature, and limb abnormalities

  Inheritance: AR Classification: STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.068).
• BP6: Variant 21-33559604-A-G is Benign according to our data. Variant chr21-33559604-A-G is described in ClinVar as Benign. ClinVar VariationId is 2908987.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.646 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.0000302 (44/1458110) while in subpopulation SAS AF = 0.000503 (43/85434). AF 95% confidence interval is 0.000383. There are 0 homozygotes in GnomAdExome4. There are 28 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAdExome4 at 44 AD gene.

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.6486A>G	p.Pro2162Pro	synonymous	Exon 6 of 12	NP_620305.3	P18583-1
	SON	NM_032195.3		c.6486A>G	p.Pro2162Pro	synonymous	Exon 6 of 7	NP_115571.3	P18583-3
	SON	NM_001291412.3		c.570A>G	p.Pro190Pro	synonymous	Exon 5 of 11	NP_001278341.1	J3QSZ5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SON	ENST00000356577.10	TSL:1 MANE Select	c.6486A>G	p.Pro2162Pro	synonymous	Exon 6 of 12	ENSP00000348984.4	P18583-1
	SON	ENST00000300278.8	TSL:1	c.6486A>G	p.Pro2162Pro	synonymous	Exon 6 of 7	ENSP00000300278.2	P18583-3
	SON	ENST00000381692.6	TSL:1	c.570A>G	p.Pro190Pro	synonymous	Exon 5 of 11	ENSP00000371111.2	J3QSZ5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000688 AC: 17 AN: 247234 AF XY: 0.000105

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000302 AC: 44 AN: 1458110 Hom.: 0 Cov.: 32 AF XY: 0.0000386 AC XY: 28 AN XY: 725324

African (AFR) AF: 0.00 AC: 0 AN: 33098

American (AMR) AF: 0.00 AC: 0 AN: 43640

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25970

East Asian (EAS) AF: 0.00 AC: 0 AN: 39678

South Asian (SAS) AF: 0.000503 AC: 43 AN: 85434

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53342

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5744

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110964

Other (OTH) AF: 0.0000166 AC: 1 AN: 60240

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000508 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	6.2
DANN	Benign	0.87
PhyloP100		0.65
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs767907159; hg19: chr21-34931910;