dbSNP rs747371296: SIMC1:p.Pro503Leu (chr5-176295106-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001308195.2(SIMC1):c.1508C>T(p.Pro503Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000109 in 1,613,232 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: 𝑓 0.00022 ( 0 hom., cov: 30)

Exomes 𝑓: 0.000098 ( 0 hom. )

Consequence

SIMC1
NM_001308195.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.09

Publications

0 publications found

Variant links:

Genes affected

SIMC1 (HGNC:24779): (SUMO interacting motifs containing 1) Enables SUMO polymer binding activity and peptidase inhibitor activity. Predicted to be involved in negative regulation of peptidase activity. Located in sarcomere. [provided by Alliance of Genome Resources, Apr 2022]

SIMC1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.115273744).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001308195.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SIMC1	NM_001308195.2	MANE Select	c.1508C>T	p.Pro503Leu	missense	Exon 3 of 10	NP_001295124.1	Q8NDZ2-5
SIMC1	NM_001308196.2		c.1451C>T	p.Pro484Leu	missense	Exon 5 of 12	NP_001295125.1	Q8NDZ2-1
SIMC1	NM_198567.6		c.206C>T	p.Pro69Leu	missense	Exon 2 of 9	NP_940969.3	Q8NDZ2-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SIMC1	ENST00000429602.7	TSL:1 MANE Select	c.1508C>T	p.Pro503Leu	missense	Exon 3 of 10	ENSP00000410552.3	Q8NDZ2-5
SIMC1	ENST00000443967.5	TSL:1	c.1451C>T	p.Pro484Leu	missense	Exon 5 of 12	ENSP00000406571.1	Q8NDZ2-1
SIMC1	ENST00000938813.1		c.1508C>T	p.Pro503Leu	missense	Exon 3 of 11	ENSP00000608872.1

Frequencies

GnomAD3 genomes

AF:

0.000217

AC:

AN:

151766

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00197

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000235

AC:

AN:

250852

AF XY:

0.000221

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00101

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000177

Gnomad OTH exome

AF:

0.000327

GnomAD4 exome

AF:

0.0000978

AC:

143

AN:

1461466

Hom.:

Cov.:

AF XY:

0.0000908

AC XY:

AN XY:

727032

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33472

American (AMR)

AF:

0.000895

AC:

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86246

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53400

Middle Eastern (MID)

AF:

0.000521

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.0000756

AC:

AN:

1111682

Other (OTH)

AF:

0.000199

AC:

AN:

60356

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

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:

0.000217

AC:

AN:

151766

Hom.:

Cov.:

AF XY:

0.000256

AC XY:

AN XY:

74084

show subpopulations

African (AFR)

AF:

0.0000242

AC:

AN:

41284

American (AMR)

AF:

0.00197

AC:

AN:

15234

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4792

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10504

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

67992

Other (OTH)

AF:

0.00

AC:

AN:

2086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.537

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:

0.000310

ExAC

AF:

0.000124

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000237

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

Uncertain

0.46

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.17

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.21

Eigen

Uncertain

0.40

Eigen_PC

Uncertain

0.38

FATHMM_MKL

Benign

0.60

LIST_S2

Uncertain

0.88

M_CAP

Benign

0.029

MetaRNN

Benign

0.12

MetaSVM

Benign

-0.77

MutationAssessor

Benign

1.5

PhyloP100

3.1

PrimateAI

Uncertain

0.66

PROVEAN

Pathogenic

-4.9

REVEL

Uncertain

0.32

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

1.0

Vest4

0.45

MutPred

0.46

Gain of catalytic residue at P484 (P = 0.0032)

MVP

0.60

MPC

2.0

ClinPred

0.58

GERP RS

4.2

Varity_R

0.072

gMVP

0.61

Mutation Taster

=90/10

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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