chr21-33559605-A-C

Variant names:

• chr21-33559605-A-C
• rs16838998
• NM_138927.4:c.6487A>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_138927.4(SON):​c.6487A>C​(p.Thr2163Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SON NM_138927.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.54

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 2 ACMG points.

• PM1: In a modified_residue Phosphothreonine (size 0) in uniprot entity SON_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17873484).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SON	NM_138927.4	c.6487A>C	p.Thr2163Pro	missense_variant	Exon 6 of 12	ENST00000356577.10	NP_620305.3
SON	NM_032195.3	c.6487A>C	p.Thr2163Pro	missense_variant	Exon 6 of 7		NP_115571.3
SON	NM_001291412.3	c.571A>C	p.Thr191Pro	missense_variant	Exon 5 of 11		NP_001278341.1
SON	NR_103797.2	n.6542A>C		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.6487A>C	p.Thr2163Pro	missense_variant	Exon 6 of 12	1	NM_138927.4	ENSP00000348984.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000404 AC: 1 AN: 247282 Hom.: 0 AF XY: 0.00000747 AC XY: 1 AN XY: 133844

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 SAS exome AF: 0.0000335

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 6.86e-7 AC: 1 AN: 1458100 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 725304

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000117

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.34
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	21
DANN	Benign	0.92
DEOGEN2	Benign	0.036	T;.;.;.
Eigen	Benign	-0.042
Eigen_PC	Benign	0.15
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.72	T;T;T;T
M_CAP	Benign	0.0082	T
MetaRNN	Benign	0.18	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N;.;N;.
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-2.5	N;D;N;D
REVEL	Benign	0.16
Sift	Benign	0.033	D;T;D;T
Sift4G	Benign	0.071	T;T;D;T
Polyphen		0.30	B;.;B;.
Vest4		0.42
MutPred		0.20		Gain of glycosylation at T2163 (P = 0.009);.;Gain of glycosylation at T2163 (P = 0.009);.;
MVP		0.44
MPC		1.7
ClinPred		0.30	T
GERP RS		5.4
Varity_R		0.31
gMVP		0.63

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs16838998; hg19: chr21-34931911;