NM_138927.4:c.6637A>G

Variant names:

• chr21-33559755-A-G
• NM_138927.4:c.6637A>G

Variant summary

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

The NM_138927.4(SON):​c.6637A>G​(p.Ser2213Gly) 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. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SON NM_138927.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.60

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]

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=0.16471577).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SON	NM_138927.4	c.6637A>G	p.Ser2213Gly	missense_variant	Exon 6 of 12	ENST00000356577.10	NP_620305.3
SON	NM_032195.3	c.6637A>G	p.Ser2213Gly	missense_variant	Exon 6 of 7		NP_115571.3
SON	NM_001291412.3	c.721A>G	p.Ser241Gly	missense_variant	Exon 5 of 11		NP_001278341.1
SON	NR_103797.2	n.6692A>G		non_coding_transcript_exon_variant	Exon 6 of 13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SON	ENST00000356577.10	c.6637A>G	p.Ser2213Gly	missense_variant	Exon 6 of 12	1	NM_138927.4	ENSP00000348984.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Dec 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces serine, which is neutral and polar, with glycine, which is neutral and non-polar, at codon 2213 of the SON protein (p.Ser2213Gly). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with SON-related conditions. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	21
DANN	Benign	0.96
DEOGEN2	Benign	0.044	T;.;.;.
Eigen	Benign	0.093
Eigen_PC	Benign	0.22
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.82	T;D;T;D
M_CAP	Benign	0.0077	T
MetaRNN	Benign	0.16	T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.55	N;.;N;.
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-2.2	N;N;N;N
REVEL	Benign	0.13
Sift	Uncertain	0.027	D;T;D;T
Sift4G	Uncertain	0.010	D;T;D;T
Polyphen		0.98	D;.;D;.
Vest4		0.24
MutPred		0.12		Loss of phosphorylation at S2213 (P = 0.071);.;Loss of phosphorylation at S2213 (P = 0.071);.;
MVP		0.55
MPC		1.1
ClinPred		0.84	D
GERP RS		5.3
Varity_R		0.26
gMVP		0.50

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: chr21-34932061;