Genetic Variant SIMC1:p.Gly12Asp (chr5-176238543-G-A) – 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.35G>A(p.Gly12Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000104 in 1,331,276 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000040 ( 0 hom., cov: 21)

Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

SIMC1
NM_001308195.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.13

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:

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=0.21198758).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SIMC1	NM_001308195.2 link	c.35G>A	p.Gly12Asp	missense_variant	Exon 1 of 10	ENST00000429602.7	NP_001295124.1	Q8NDZ2-5B4DRM7
SIMC1	NM_198567.6 link	c.35G>A	p.Gly12Asp	missense_variant	Exon 1 of 9		NP_940969.3	Q8NDZ2-3
SIMC1	NM_001308196.2 link	c.-231G>A		5_prime_UTR_variant	Exon 1 of 12		NP_001295125.1	Q8NDZ2-1B4DRM7
SIMC1	NR_131772.2 link	n.120G>A		non_coding_transcript_exon_variant	Exon 1 of 10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SIMC1	ENST00000429602.7 link	c.35G>A	p.Gly12Asp	missense_variant	Exon 1 of 10	1	NM_001308195.2	ENSP00000410552.3		Q8NDZ2-5

Frequencies

GnomAD3 genomes

AF:

0.0000398

AC:

AN:

150886

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:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000887

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.000112

AC:

132

AN:

1180390

Hom.:

Cov.:

AF XY:

0.000124

AC XY:

AN XY:

578654

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

22894

American (AMR)

AF:

0.00

AC:

AN:

15338

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

17592

East Asian (EAS)

AF:

0.00

AC:

AN:

23478

South Asian (SAS)

AF:

0.00

AC:

AN:

51396

European-Finnish (FIN)

AF:

0.00

AC:

AN:

38836

Middle Eastern (MID)

AF:

0.000318

AC:

AN:

3144

European-Non Finnish (NFE)

AF:

0.000126

AC:

121

AN:

962136

Other (OTH)

AF:

0.000219

AC:

AN:

45576

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.418

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000398

AC:

AN:

150886

Hom.:

Cov.:

AF XY:

0.0000815

AC XY:

AN XY:

73626

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

41264

American (AMR)

AF:

0.00

AC:

AN:

15156

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3456

East Asian (EAS)

AF:

0.00

AC:

AN:

5144

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10128

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000887

AC:

AN:

67610

Other (OTH)

AF:

0.00

AC:

AN:

2072

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.342

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000146

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Sep 08, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.35G>A (p.G12D) alteration is located in exon 1 (coding exon 1) of the SIMC1 gene. This alteration results from a G to A substitution at nucleotide position 35, causing the glycine (G) at amino acid position 12 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.42

CADD

Uncertain

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.0049

.;.;T

Eigen

Benign

0.089

Eigen_PC

Benign

-0.024

FATHMM_MKL

Benign

0.49

LIST_S2

Benign

0.45

T;.;T

M_CAP

Pathogenic

0.68

MetaRNN

Benign

0.21

T;T;T

MetaSVM

Benign

-1.1

PhyloP100

3.1

PROVEAN

Benign

-0.65

N;N;N

REVEL

Benign

0.12

Sift

Pathogenic

0.0

D;D;T

Sift4G

Pathogenic

0.0

D;D;T

Polyphen

1.0

D;D;.

Vest4

0.36

MutPred

0.16

Loss of sheet (P = 0.0457);Loss of sheet (P = 0.0457);Loss of sheet (P = 0.0457);

MVP

0.34

MPC

2.4

ClinPred

0.63

GERP RS

2.0

PromoterAI

0.036

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

gMVP

0.057

Mutation Taster

=91/9

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

Loading publications...

5-176238543-G-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over