Genetic Variant NM_005067.7:c.80C>G (chr3-150762770-G-C) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). 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 0.00050 ( 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

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.03308311).

BS2

High AC in GnomAd4 at 74 AD gene.

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>G	p.Pro27Arg	missense	Exon 1 of 2	NP_005058.3
SIAH2-AS1	NR_187305.1		n.310+363G>C		intron	N/A
SIAH2-AS1	NR_187306.1		n.113+363G>C		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SIAH2	ENST00000312960.4	TSL:1 MANE Select	c.80C>G	p.Pro27Arg	missense	Exon 1 of 2	ENSP00000322457.3	O43255
SIAH2	ENST00000936558.1		c.80C>G	p.Pro27Arg	missense	Exon 1 of 3	ENSP00000606617.1
SIAH2	ENST00000482706.1	TSL:3	c.-99-200C>G		intron	N/A	ENSP00000417619.1	C9J9D7

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

GnomAD2 exomes

AF:

0.000324

AC:

AN:

67914

AF XY:

0.000365

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 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

African (AFR)

AF:

0.000234

AC:

AN:

21354

American (AMR)

AF:

0.0000842

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:

0.000152

AC:

AN:

32936

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2582

European-Non Finnish (NFE)

AF:

0.000897

AC:

804

AN:

896722

Other (OTH)

AF:

0.000332

AC:

AN:

39214

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

139

186

232

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

114

152

190

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000496

AC:

AN:

149254

Hom.:

Cov.:

AF XY:

0.000412

AC XY:

AN XY:

72772

show subpopulations

African (AFR)

AF:

0.0000973

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:

0.000105

AC:

AN:

9526

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.00103

AC:

AN:

66920

Other (OTH)

AF:

0.00

AC:

AN:

2056

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.000468

ExAC

AF:

0.000267

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.47

CADD

Benign

(source)

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

PhyloP100

0.026

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

PromoterAI

-0.021

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.13

gMVP

0.44

Mutation Taster

=94/6

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over