Genetic Variant SIAH2:p.Asn12Ser (chr3-150762815-T-C) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_005067.7(SIAH2):c.35A>G(p.Asn12Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000839 in 1,073,248 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 31)

Exomes 𝑓: 0.0000084 ( 0 hom. )

Consequence

SIAH2
NM_005067.7 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.0200

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.05826378).

BS2

High AC in GnomAdExome4 at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SIAH2	NM_005067.7 link	c.35A>G	p.Asn12Ser	missense_variant	Exon 1 of 2	ENST00000312960.4	NP_005058.3	O43255
SIAH2-AS1	NR_187305.1 link	n.310+408T>C		intron_variant	Intron 2 of 2
SIAH2-AS1	NR_187306.1 link	n.113+408T>C		intron_variant	Intron 2 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SIAH2	ENST00000312960.4 link	c.35A>G	p.Asn12Ser	missense_variant	Exon 1 of 2	1	NM_005067.7	ENSP00000322457.3	O43255
SIAH2	ENST00000482706.1 link	c.-99-245A>G		intron_variant	Intron 1 of 2	3		ENSP00000417619.1	C9J9D7
SIAH2	ENST00000472885.1 link	n.338-245A>G		intron_variant	Intron 1 of 1	4
SIAH2-AS1	ENST00000663257.1 link	n.255+408T>C		intron_variant	Intron 1 of 2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000112

AC:

AN:

89582

Hom.:

AF XY:

0.0000198

AC XY:

AN XY:

50582

show subpopulations

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:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000219

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000839

AC:

AN:

1073248

Hom.:

Cov.:

AF XY:

0.0000136

AC XY:

AN XY:

513176

show subpopulations

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:

0.000163

Gnomad4 FIN exome

AF:

0.0000291

Gnomad4 NFE exome

AF:

0.00000222

Gnomad4 OTH exome

AF:

0.0000251

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000973

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jul 06, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.35A>G (p.N12S) alteration is located in exon 1 (coding exon 1) of the SIAH2 gene. This alteration results from a A to G substitution at nucleotide position 35, causing the asparagine (N) at amino acid position 12 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

Benign

0.054

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.72

CADD

Benign

DANN

Benign

0.58

DEOGEN2

Benign

0.085

Eigen

Benign

-0.98

Eigen_PC

Benign

-0.80

FATHMM_MKL

Benign

0.092

LIST_S2

Benign

0.53

M_CAP

Uncertain

0.21

MetaRNN

Benign

0.058

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

PrimateAI

Pathogenic

0.86

PROVEAN

Benign

-0.12

REVEL

Benign

0.048

Sift

Benign

0.37

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.084

MutPred

0.18

Gain of glycosylation at S10 (P = 0.0136);

MVP

0.26

MPC

0.77

ClinPred

0.021

GERP RS

-0.15

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.029

gMVP

0.23

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

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over