dbSNP rs769999877: SIAH2:p.Ser16Thr (chr3-150762803-C-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate

The NM_005067.7(SIAH2):c.47G>C(p.Ser16Thr) 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S16N) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

SIAH2
NM_005067.7 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.744

Variant links:

Genes affected

SIAH2 (HGNC:10858): (siah E3 ubiquitin protein ligase 2) This gene encodes a protein that is a member of the seven in absentia homolog (SIAH) family. The protein is an E3 ligase and is involved in ubiquitination and proteasome-mediated degradation of specific proteins. The activity of this ubiquitin ligase has been implicated in regulating cellular response to hypoxia. [provided by RefSeq, Jul 2008]

SIAH2 links:

SIAH2-AS1 (HGNC:40526): (SIAH2 antisense RNA 1)

SIAH2-AS1 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM1

In a mutagenesis_site Strongly reduced phosphorylation by DYRK2; when associated with A-26; A-28; A-68 and A-119. (size 0) in uniprot entity SIAH2_HUMAN

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.083726704).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SIAH2	NM_005067.7 link	c.47G>C	p.Ser16Thr	missense_variant	Exon 1 of 2	ENST00000312960.4	NP_005058.3	O43255
SIAH2-AS1	NR_187305.1 link	n.310+396C>G		intron_variant	Intron 2 of 2
SIAH2-AS1	NR_187306.1 link	n.113+396C>G		intron_variant	Intron 2 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SIAH2	ENST00000312960.4 link	c.47G>C	p.Ser16Thr	missense_variant	Exon 1 of 2	1	NM_005067.7	ENSP00000322457.3	O43255
SIAH2	ENST00000482706.1 link	c.-99-233G>C		intron_variant	Intron 1 of 2	3		ENSP00000417619.1	C9J9D7
SIAH2	ENST00000472885.1 link	n.338-233G>C		intron_variant	Intron 1 of 1	4
SIAH2-AS1	ENST00000663257.1 link	n.255+396C>G		intron_variant	Intron 1 of 2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1077336

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

515174

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000196

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.59

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Benign

0.10

Eigen

Benign

-0.55

Eigen_PC

Benign

-0.37

FATHMM_MKL

Benign

0.57

LIST_S2

Benign

0.32

M_CAP

Pathogenic

0.34

MetaRNN

Benign

0.084

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.34

PrimateAI

Pathogenic

0.86

PROVEAN

Benign

-0.39

REVEL

Benign

0.041

Sift

Benign

0.66

Sift4G

Benign

0.57

Polyphen

0.0050

Vest4

0.086

MutPred

0.18

Loss of glycosylation at P20 (P = 0.0018);

MVP

0.28

MPC

0.88

ClinPred

0.34

GERP RS

3.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.077

gMVP

0.35

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over