21-33546297-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_138927.4(SON):c.162G>C(p.Arg54Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: SON NM_138927.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.40

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2204431).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SON	NM_138927.4	c.162G>C	p.Arg54Ser	missense_variant	2/12	ENST00000356577.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SON	ENST00000356577.10	c.162G>C	p.Arg54Ser	missense_variant	2/12	1	NM_138927.4	P3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 08, 2022

The c.162G>C (p.R54S) alteration is located in exon 2 (coding exon 2) of the SON gene. This alteration results from a G to C substitution at nucleotide position 162, causing the arginine (R) at amino acid position 54 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.60
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Benign	0.037	T;.;.;.
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.91	D;D;D;D
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.22	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.90	L;.;L;L
MutationTaster	Benign	0.87	N;N;N;N;N
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-2.4	N;D;N;N
REVEL	Benign	0.14
Sift	Uncertain	0.0030	D;D;D;D
Sift4G	Pathogenic	0.0	D;T;D;D
Polyphen		0.99	D;.;D;D
Vest4		0.75
MutPred		0.21		Gain of loop (P = 0.0079);Gain of loop (P = 0.0079);Gain of loop (P = 0.0079);Gain of loop (P = 0.0079);
MVP		0.74
MPC		0.16
ClinPred		0.80	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.37
gMVP		0.48

Splicing

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr21-34918603;