5-176313733-G-A

Variant names:

• chr5-176313733-G-A
• rs200331366
• NM_001308195.2:c.1777G>A

Variant summary

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

The NM_001308195.2(SIMC1):​c.1777G>A​(p.Val593Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000138 in 1,613,750 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00025 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00013 (0 hom.)
• Consequence: SIMC1 NM_001308195.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.40
• Publications: 0 publications found

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]

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.09142792).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SIMC1	NM_001308195.2	MANE Select	c.1777G>A	p.Val593Ile	missense	Exon 5 of 10	NP_001295124.1	Q8NDZ2-5
	SIMC1	NM_001308196.2		c.1720G>A	p.Val574Ile	missense	Exon 7 of 12	NP_001295125.1	Q8NDZ2-1
	SIMC1	NM_198567.6		c.475G>A	p.Val159Ile	missense	Exon 4 of 9	NP_940969.3	Q8NDZ2-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SIMC1	ENST00000429602.7	TSL:1 MANE Select	c.1777G>A	p.Val593Ile	missense	Exon 5 of 10	ENSP00000410552.3	Q8NDZ2-5
	SIMC1	ENST00000443967.5	TSL:1	c.1720G>A	p.Val574Ile	missense	Exon 7 of 12	ENSP00000406571.1	Q8NDZ2-1
	SIMC1	ENST00000332772.4	TSL:1	c.103G>A	p.Val35Ile	missense	Exon 2 of 7	ENSP00000331311.4	Q8NDZ2-4

Frequencies

GnomAD3 genomes AF: 0.000250 AC: 38 AN: 152066 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00210

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000139 AC: 35 AN: 251082 AF XY: 0.000133

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000434

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000326

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000115

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000126 AC: 184 AN: 1461684 Hom.: 0 Cov.: 31 AF XY: 0.000114 AC XY: 83 AN XY: 727124

African (AFR) AF: 0.000149 AC: 5 AN: 33478

American (AMR) AF: 0.000425 AC: 19 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39700

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86256

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.000132 AC: 147 AN: 1111852

Other (OTH) AF: 0.0000994 AC: 6 AN: 60372

GnomAD4 genome AF: 0.000250 AC: 38 AN: 152066 Hom.: 0 Cov.: 32 AF XY: 0.000377 AC XY: 28 AN XY: 74280

African (AFR) AF: 0.0000242 AC: 1 AN: 41402

American (AMR) AF: 0.00210 AC: 32 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10596

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68016

Other (OTH) AF: 0.000478 AC: 1 AN: 2090

Alfa AF: 0.0000868 Hom.: 0

Bravo AF: 0.000223

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000741 AC: 9

EpiCase AF: 0.00

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.059	T
Eigen	Benign	0.087
Eigen_PC	Benign	0.14
FATHMM_MKL	Benign	0.70	D
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.091	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	L
PhyloP100		4.4
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.59	N
REVEL	Benign	0.076
Sift	Benign	0.087	T
Sift4G	Benign	0.30	T
Polyphen		0.40	B
Vest4		0.26
MVP		0.50
MPC		0.17
ClinPred		0.056	T
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.039
gMVP		0.19
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

dbSNP: rs200331366; hg19: chr5-175740736; COSMIC: COSV57905569; COSMIC: COSV57905569;