Genetic Variant NM_198849.3:c.251A>G (chr13-45783942-T-C) – 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_198849.3(SIAH3):c.251A>G(p.His84Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000417 in 1,605,728 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 (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000044 ( 0 hom. )

Consequence

SIAH3
NM_198849.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.18

Publications

0 publications found

Variant links:

Genes affected

SIAH3 (HGNC:30553): (siah E3 ubiquitin protein ligase family member 3) Predicted to enable ubiquitin conjugating enzyme binding activity and ubiquitin protein ligase activity. Involved in negative regulation of protein targeting to mitochondrion and regulation of protein stability. Located in mitochondrion and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

SIAH3 links:

Genome browser will be placed here

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=0.17429596).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198849.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SIAH3	NM_198849.3	MANE Select	c.251A>G	p.His84Arg	missense	Exon 2 of 2	NP_942146.2	Q8IW03

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SIAH3	ENST00000400405.4	TSL:1 MANE Select	c.251A>G	p.His84Arg	missense	Exon 2 of 2	ENSP00000383256.2	Q8IW03

Frequencies

GnomAD3 genomes

AF:

0.0000199

AC:

AN:

150904

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:

0.000195

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000295

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000251

AC:

AN:

238972

AF XY:

0.0000386

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000560

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000462

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000440

AC:

AN:

1454824

Hom.:

Cov.:

AF XY:

0.0000456

AC XY:

AN XY:

723100

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33454

American (AMR)

AF:

0.00

AC:

AN:

44486

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25492

East Asian (EAS)

AF:

0.00

AC:

AN:

39678

South Asian (SAS)

AF:

0.00

AC:

AN:

84658

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52220

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5678

European-Non Finnish (NFE)

AF:

0.0000541

AC:

AN:

1109010

Other (OTH)

AF:

0.0000665

AC:

AN:

60148

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

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

AF:

0.0000199

AC:

AN:

150904

Hom.:

Cov.:

AF XY:

0.0000272

AC XY:

AN XY:

73612

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

40992

American (AMR)

AF:

0.00

AC:

AN:

15164

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3456

East Asian (EAS)

AF:

0.000195

AC:

AN:

5132

South Asian (SAS)

AF:

0.00

AC:

AN:

4718

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10452

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000295

AC:

AN:

67702

Other (OTH)

AF:

0.00

AC:

AN:

2068

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

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:

0.0000868

Hom.:

Bravo

AF:

0.0000340

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000118

AC:

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

Benign

0.081

BayesDel_addAF

Benign

-0.052

BayesDel_noAF

Benign

-0.31

CADD

Benign

(source)

DANN

Benign

0.92

DEOGEN2

Benign

0.016

Eigen

Benign

0.17

Eigen_PC

Benign

0.069

FATHMM_MKL

Uncertain

0.84

LIST_S2

Benign

0.44

M_CAP

Benign

0.0081

MetaRNN

Benign

0.17

MetaSVM

Benign

-0.98

MutationAssessor

Benign

1.8

PhyloP100

1.2

PrimateAI

Benign

0.45

PROVEAN

Benign

-0.060

REVEL

Uncertain

0.36

Sift

Benign

0.43

Sift4G

Uncertain

0.021

Polyphen

1.0

Vest4

0.22

MVP

0.061

MPC

0.32

ClinPred

0.50

GERP RS

4.6

Varity_R

0.069

gMVP

0.19

Mutation Taster

=96/4

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