Genetic Variant SIAH2:p.Pro27Gln (chr3-150762770-G-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_005067.7(SIAH2):c.80C>A(p.Pro27Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000067 in 149,254 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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. P27L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000067 ( 0 hom., 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: 0.0260

Publications

2 publications found

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 was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.0977729).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005067.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SIAH2	NM_005067.7	MANE Select	c.80C>A	p.Pro27Gln	missense	Exon 1 of 2	NP_005058.3
SIAH2-AS1	NR_187305.1		n.310+363G>T		intron	N/A
SIAH2-AS1	NR_187306.1		n.113+363G>T		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SIAH2	ENST00000312960.4	TSL:1 MANE Select	c.80C>A	p.Pro27Gln	missense	Exon 1 of 2	ENSP00000322457.3	O43255
SIAH2	ENST00000936558.1		c.80C>A	p.Pro27Gln	missense	Exon 1 of 3	ENSP00000606617.1
SIAH2	ENST00000482706.1	TSL:3	c.-99-200C>A		intron	N/A	ENSP00000417619.1	C9J9D7

Frequencies

GnomAD3 genomes

AF:

0.00000670

AC:

AN:

149254

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000149

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1059856

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

506830

African (AFR)

AF:

0.00

AC:

AN:

21354

American (AMR)

AF:

0.00

AC:

AN:

11882

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

11050

East Asian (EAS)

AF:

0.00

AC:

AN:

21300

South Asian (SAS)

AF:

0.00

AC:

AN:

22814

European-Finnish (FIN)

AF:

0.00

AC:

AN:

32936

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2582

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

896724

Other (OTH)

AF:

0.00

AC:

AN:

39214

GnomAD4 genome

AF:

0.00000670

AC:

AN:

149254

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

72772

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41092

American (AMR)

AF:

0.00

AC:

AN:

15046

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3436

East Asian (EAS)

AF:

0.00

AC:

AN:

5126

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9526

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000149

AC:

AN:

66920

Other (OTH)

AF:

0.00

AC:

AN:

2056

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.625

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.083

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.56

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.091

Eigen

Benign

-0.54

Eigen_PC

Benign

-0.47

FATHMM_MKL

Benign

0.29

LIST_S2

Benign

0.41

M_CAP

Uncertain

0.22

MetaRNN

Benign

0.098

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.69

PhyloP100

0.026

PrimateAI

Pathogenic

0.81

PROVEAN

Benign

-0.37

REVEL

Benign

0.029

Sift

Benign

0.43

Sift4G

Benign

0.14

Polyphen

0.0010

Vest4

0.12

MutPred

0.25

Loss of glycosylation at P32 (P = 0.006)

MVP

0.24

MPC

0.89

ClinPred

0.092

GERP RS

0.24

PromoterAI

0.024

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.072

gMVP

0.44

Mutation Taster

=92/8

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over