Genetic Variant SIMC1:p.Ala19Asp (chr5-176238564-C-A) – 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_001308195.2(SIMC1):c.56C>A(p.Ala19Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 21)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

SIMC1
NM_001308195.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.24

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:

ENSG00000283235 (HGNC:):

ENSG00000283235 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=0.0874663).

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.56C>A	p.Ala19Asp	missense	Exon 1 of 10	NP_001295124.1	Q8NDZ2-5
SIMC1	NM_198567.6		c.56C>A	p.Ala19Asp	missense	Exon 1 of 9	NP_940969.3	Q8NDZ2-3
SIMC1	NM_001308196.2		c.-210C>A		5_prime_UTR	Exon 1 of 12	NP_001295125.1	Q8NDZ2-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SIMC1	ENST00000429602.7	TSL:1 MANE Select	c.56C>A	p.Ala19Asp	missense	Exon 1 of 10	ENSP00000410552.3	Q8NDZ2-5
SIMC1	ENST00000443967.5	TSL:1	c.-210C>A		5_prime_UTR	Exon 1 of 12	ENSP00000406571.1	Q8NDZ2-1
SIMC1	ENST00000938813.1		c.56C>A	p.Ala19Asp	missense	Exon 1 of 11	ENSP00000608872.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

1158274

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

566024

African (AFR)

AF:

0.00

AC:

AN:

22360

American (AMR)

AF:

0.00

AC:

AN:

11514

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

16114

East Asian (EAS)

AF:

0.00

AC:

AN:

23864

South Asian (SAS)

AF:

0.00

AC:

AN:

45066

European-Finnish (FIN)

AF:

0.00

AC:

AN:

37016

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3050

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

954510

Other (OTH)

AF:

0.00

AC:

AN:

44780

GnomAD4 genome

Cov.:

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

0.15

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.59

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.0084

Eigen

Benign

-0.67

Eigen_PC

Benign

-0.66

FATHMM_MKL

Benign

0.21

LIST_S2

Benign

0.33

M_CAP

Uncertain

0.092

MetaRNN

Benign

0.087

MetaSVM

Benign

-1.0

PhyloP100

1.2

PROVEAN

Benign

-0.33

REVEL

Benign

0.025

Sift

Benign

0.32

Sift4G

Benign

0.46

Polyphen

0.014

Vest4

0.20

MutPred

0.18

Gain of solvent accessibility (P = 0.0156)

MVP

0.19

MPC

1.5

ClinPred

0.25

GERP RS

2.0

PromoterAI

0.021

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

gMVP

0.11

Mutation Taster

=87/13

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