Variant 3-150762770-G-C details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_005067.7(SIAH2):c.80C>G(p.Pro27Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000746 in 1,209,108 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: 𝑓 0.00050 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00078 ( 0 hom. )

Consequence

SIAH2
NM_005067.7 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.0260

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=0.03308311).

BS2

High AC in GnomAd4 at 74 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
SIAH2	NM_005067.7 linkuse as main transcript	c.80C>G	p.Pro27Arg	missense_variant	1/2	ENST00000312960.4	NP_005058.3
SIAH2-AS1	XR_007096130.1 linkuse as main transcript	n.471+363G>C		intron_variant, non_coding_transcript_variant
SIAH2-AS1	XR_007096129.1 linkuse as main transcript	n.471+363G>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
SIAH2	ENST00000312960.4 linkuse as main transcript	c.80C>G	p.Pro27Arg	missense_variant	1/2	1	NM_005067.7	ENSP00000322457	P1
SIAH2-AS1	ENST00000663257.1 linkuse as main transcript	n.255+363G>C		intron_variant, non_coding_transcript_variant
SIAH2	ENST00000482706.1 linkuse as main transcript	c.-99-200C>G		intron_variant		3		ENSP00000417619
SIAH2	ENST00000472885.1 linkuse as main transcript	n.338-200C>G		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes

AF:

0.000496

AC:

AN:

149254

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000973

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000105

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00103

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000324

AC:

AN:

67914

Hom.:

AF XY:

0.000365

AC XY:

AN XY:

38342

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000158

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000820

Gnomad NFE exome

AF:

0.000575

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000781

AC:

828

AN:

1059854

Hom.:

Cov.:

AF XY:

0.000768

AC XY:

389

AN XY:

506830

show subpopulations

Gnomad4 AFR exome

AF:

0.000234

Gnomad4 AMR exome

AF:

0.0000842

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000152

Gnomad4 NFE exome

AF:

0.000897

Gnomad4 OTH exome

AF:

0.000332

GnomAD4 genome

AF:

0.000496

AC:

AN:

149254

Hom.:

Cov.:

AF XY:

0.000412

AC XY:

AN XY:

72772

show subpopulations

Gnomad4 AFR

AF:

0.0000973

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000105

Gnomad4 NFE

AF:

0.00103

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.000468

ExAC

AF:

0.000267

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 20, 2021

The c.80C>G (p.P27R) alteration is located in exon 1 (coding exon 1) of the SIAH2 gene. This alteration results from a C to G substitution at nucleotide position 80, causing the proline (P) at amino acid position 27 to be replaced by an arginine (R). 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

0.11

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.47

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Benign

0.081

Eigen

Benign

-0.50

Eigen_PC

Benign

-0.44

FATHMM_MKL

Benign

0.39

LIST_S2

Benign

0.48

M_CAP

Uncertain

0.22

MetaRNN

Benign

0.033

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.34

MutationTaster

Benign

0.72

PrimateAI

Pathogenic

0.83

PROVEAN

Benign

-0.51

REVEL

Benign

0.017

Sift

Uncertain

0.017

Sift4G

Benign

0.13

Polyphen

0.036

Vest4

0.17

MVP

0.27

MPC

1.0

ClinPred

0.036

GERP RS

0.24

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.13

gMVP

0.44

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