rs13047599

Positions:

• chr21-33553954-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_138927.4(SON):​c.4723C>T​(p.Arg1575Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.684 in 1,613,556 control chromosomes in the GnomAD database, including 378,461 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.70 (37793 hom., cov: 32)
  • Exomes 𝑓: 0.68 (340668 hom.)
• Consequence: SON NM_138927.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.0430

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=9.871352E-7).
• BP6: Variant 21-33553954-C-T is Benign according to our data. Variant chr21-33553954-C-T is described in ClinVar as [Benign]. Clinvar id is 1170805.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.76 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SON	NM_138927.4	c.4723C>T	p.Arg1575Cys	missense_variant	3/12	ENST00000356577.10	NP_620305.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SON	ENST00000356577.10	c.4723C>T	p.Arg1575Cys	missense_variant	3/12	1	NM_138927.4	ENSP00000348984	P3

Frequencies

GnomAD3 genomes AF: 0.704 AC: 107012 AN: 151930 Hom.: 37772 Cov.: 32

Gnomad AFR AF: 0.767

Gnomad AMI AF: 0.683

Gnomad AMR AF: 0.707

Gnomad ASJ AF: 0.582

Gnomad EAS AF: 0.731

Gnomad SAS AF: 0.655

Gnomad FIN AF: 0.710

Gnomad MID AF: 0.544

Gnomad NFE AF: 0.674

Gnomad OTH AF: 0.676

GnomAD3 exomes AF: 0.678 AC: 170442 AN: 251266 Hom.: 58198 AF XY: 0.675 AC XY: 91699 AN XY: 135842

Gnomad AFR exome AF: 0.772

Gnomad AMR exome AF: 0.669

Gnomad ASJ exome AF: 0.590

Gnomad EAS exome AF: 0.742

Gnomad SAS exome AF: 0.644

Gnomad FIN exome AF: 0.703

Gnomad NFE exome AF: 0.670

Gnomad OTH exome AF: 0.673

GnomAD4 exome AF: 0.682 AC: 996696 AN: 1461508 Hom.: 340668 Cov.: 56 AF XY: 0.680 AC XY: 494193 AN XY: 727086

Gnomad4 AFR exome AF: 0.768

Gnomad4 AMR exome AF: 0.671

Gnomad4 ASJ exome AF: 0.593

Gnomad4 EAS exome AF: 0.741

Gnomad4 SAS exome AF: 0.645

Gnomad4 FIN exome AF: 0.696

Gnomad4 NFE exome AF: 0.682

Gnomad4 OTH exome AF: 0.683

GnomAD4 genome AF: 0.704 AC: 107074 AN: 152048 Hom.: 37793 Cov.: 32 AF XY: 0.707 AC XY: 52514 AN XY: 74316

Gnomad4 AFR AF: 0.767

Gnomad4 AMR AF: 0.707

Gnomad4 ASJ AF: 0.582

Gnomad4 EAS AF: 0.731

Gnomad4 SAS AF: 0.653

Gnomad4 FIN AF: 0.710

Gnomad4 NFE AF: 0.674

Gnomad4 OTH AF: 0.671

Alfa AF: 0.674 Hom.: 69279

Bravo AF: 0.706

TwinsUK AF: 0.689 AC: 2556

ALSPAC AF: 0.676 AC: 2606

ESP6500AA AF: 0.766 AC: 3377

ESP6500EA AF: 0.673 AC: 5791

ExAC AF: 0.678 AC: 82291

Asia WGS AF: 0.691 AC: 2404 AN: 3478

EpiCase AF: 0.665

EpiControl AF: 0.665

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 10, 2022	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

ZTTK syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 15, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.051
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	6.4
DANN	Benign	0.040
DEOGEN2	Benign	0.015	T;.;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.031	N
LIST_S2	Benign	0.16	T;T;T
MetaRNN	Benign	9.9e-7	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-1.7	N;N;N
MutationTaster	Benign	1.0	P;P;P;P;P
PrimateAI	Benign	0.38	T
PROVEAN	Benign	2.0	N;N;N
REVEL	Benign	0.029
Sift	Benign	0.66	T;T;T
Sift4G	Benign	0.44	T;T;T
Polyphen		0.0	B;B;B
Vest4		0.049
MPC		0.12
ClinPred		0.00019	T
GERP RS		0.84
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3
Varity_R		0.050
gMVP		0.10

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs13047599; hg19: chr21-34926260; COSMIC: COSV51652492; COSMIC: COSV51652492;