Genetic Variant NM_005067.7:c.224C>T (chr3-150762626-G-A) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_005067.7(SIAH2):c.224C>T(p.Thr75Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000096 in 1,457,690 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000096 ( 0 hom. )

Consequence

SIAH2
NM_005067.7 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.89

Publications

0 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: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.1513978).

BS2

High AC in GnomAdExome4 at 14 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.224C>T	p.Thr75Ile	missense	Exon 1 of 2	NP_005058.3
SIAH2-AS1	NR_187305.1		n.310+219G>A		intron	N/A
SIAH2-AS1	NR_187306.1		n.113+219G>A		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SIAH2	ENST00000312960.4	TSL:1 MANE Select	c.224C>T	p.Thr75Ile	missense	Exon 1 of 2	ENSP00000322457.3	O43255
SIAH2	ENST00000936558.1		c.224C>T	p.Thr75Ile	missense	Exon 1 of 3	ENSP00000606617.1
SIAH2	ENST00000482706.1	TSL:3	c.-99-56C>T		intron	N/A	ENSP00000417619.1	C9J9D7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000126

AC:

AN:

238360

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000894

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000960

AC:

AN:

1457690

Hom.:

Cov.:

AF XY:

0.00000690

AC XY:

AN XY:

725034

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33338

American (AMR)

AF:

0.0000676

AC:

AN:

44396

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26046

East Asian (EAS)

AF:

0.00

AC:

AN:

39350

South Asian (SAS)

AF:

0.00

AC:

AN:

85882

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52030

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5740

European-Non Finnish (NFE)

AF:

0.00000900

AC:

AN:

1110744

Other (OTH)

AF:

0.0000166

AC:

AN:

60164

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.0000248

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

Pathogenic

0.74

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.39

CADD

Uncertain

(source)

DANN

Benign

0.92

DEOGEN2

Benign

0.11

Eigen

Benign

-0.23

Eigen_PC

Benign

-0.070

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.95

M_CAP

Benign

0.012

MetaRNN

Benign

0.15

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.3

PhyloP100

9.9

PrimateAI

Pathogenic

0.95

PROVEAN

Benign

-1.3

REVEL

Benign

0.23

Sift

Benign

0.87

Sift4G

Benign

0.18

Polyphen

0.013

Vest4

0.37

MutPred

0.45

Loss of glycosylation at S76 (P = 0.0261)

MVP

0.31

MPC

1.1

ClinPred

0.23

GERP RS

4.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.55

gMVP

0.22

Mutation Taster

=27/73

disease causing

(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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over