21-33550696-G-A

Variant names:

• chr21-33550696-G-A
• rs192269145
• NM_138927.4:c.1465G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_138927.4(SON):​c.1465G>A​(p.Val489Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,838 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V489L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SON NM_138927.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.545
• 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]

MIR6501 (HGNC:50033): (microRNA 6501) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.04197374).

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.1465G>A	p.Val489Ile	missense	Exon 3 of 12	NP_620305.3	P18583-1
	SON	NM_032195.3		c.1465G>A	p.Val489Ile	missense	Exon 3 of 7	NP_115571.3	P18583-3
	SON	NM_001291411.2		c.1465G>A	p.Val489Ile	missense	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.1465G>A	p.Val489Ile	missense	Exon 3 of 12	ENSP00000348984.4	P18583-1
	SON	ENST00000300278.8	TSL:1	c.1465G>A	p.Val489Ile	missense	Exon 3 of 7	ENSP00000300278.2	P18583-3
	SON	ENST00000381692.6	TSL:1	c.244+4317G>A		intron	N/A	ENSP00000371111.2	J3QSZ5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251336 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

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: 6.84e-7 AC: 1 AN: 1461838 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 727216

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53400

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111984

Other (OTH) AF: 0.00 AC: 0 AN: 60388

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	15
DANN	Benign	0.97
DEOGEN2	Benign	0.017	T
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.51
FATHMM_MKL	Benign	0.37	N
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.0058	T
MetaRNN	Benign	0.042	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.46	N
PhyloP100		0.55
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.20	N
REVEL	Benign	0.0070
Sift	Benign	0.43	T
Sift4G	Benign	0.21	T
Polyphen		0.14	B
Vest4		0.061
MutPred		0.32		Loss of phosphorylation at T486 (P = 0.1406)
MVP		0.19
MPC		0.091
ClinPred		0.046	T
GERP RS		1.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.027
gMVP		0.051
Mutation Taster		=94/6	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs192269145; hg19: chr21-34923002;