NM_001308195.2:c.1484C>T

Variant names:

• chr5-176295082-C-T
• NM_001308195.2:c.1484C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001308195.2(SIMC1):​c.1484C>T​(p.Thr495Ile) 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. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T495A) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 30)
• Consequence: SIMC1 NM_001308195.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.103
• 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: 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=0.115450054).

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.1484C>T	p.Thr495Ile	missense	Exon 3 of 10	NP_001295124.1	Q8NDZ2-5
	SIMC1	NM_001308196.2		c.1427C>T	p.Thr476Ile	missense	Exon 5 of 12	NP_001295125.1	Q8NDZ2-1
	SIMC1	NM_198567.6		c.182C>T	p.Thr61Ile	missense	Exon 2 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.1484C>T	p.Thr495Ile	missense	Exon 3 of 10	ENSP00000410552.3	Q8NDZ2-5
	SIMC1	ENST00000443967.5	TSL:1	c.1427C>T	p.Thr476Ile	missense	Exon 5 of 12	ENSP00000406571.1	Q8NDZ2-1
	SIMC1	ENST00000938813.1		c.1484C>T	p.Thr495Ile	missense	Exon 3 of 11	ENSP00000608872.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 30

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	0.32
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	17
DANN	Benign	0.94
DEOGEN2	Benign	0.021	T
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.52
FATHMM_MKL	Benign	0.021	N
LIST_S2	Benign	0.33	T
M_CAP	Benign	0.0036	T
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N
PhyloP100		0.10
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.049
Sift	Benign	0.38	T
Sift4G	Benign	0.48	T
Polyphen		0.12	B
Vest4		0.24
MutPred		0.33		Loss of loop (P = 0.0512)
MVP		0.26
MPC		1.1
ClinPred		0.029	T
GERP RS		2.3
Varity_R		0.048
gMVP		0.27
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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

hg19: chr5-175722085;