NM_001308195.2:c.56C>T

Variant names:

• chr5-176238564-C-T
• rs2113088255
• NM_001308195.2:c.56C>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.56C>T​(p.Ala19Val) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A19D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 21)
  • Exomes 𝑓: 8.6e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SIMC1 NM_001308195.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.24
• 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]

ENSG00000283235 (HGNC:):

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=0.074539185).

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.56C>T	p.Ala19Val	missense	Exon 1 of 10	NP_001295124.1	Q8NDZ2-5
	SIMC1	NM_198567.6		c.56C>T	p.Ala19Val	missense	Exon 1 of 9	NP_940969.3	Q8NDZ2-3
	SIMC1	NM_001308196.2		c.-210C>T		5_prime_UTR	Exon 1 of 12	NP_001295125.1	Q8NDZ2-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SIMC1	ENST00000429602.7	TSL:1 MANE Select	c.56C>T	p.Ala19Val	missense	Exon 1 of 10	ENSP00000410552.3	Q8NDZ2-5
	SIMC1	ENST00000443967.5	TSL:1	c.-210C>T		5_prime_UTR	Exon 1 of 12	ENSP00000406571.1	Q8NDZ2-1
	SIMC1	ENST00000938813.1		c.56C>T	p.Ala19Val	missense	Exon 1 of 11	ENSP00000608872.1

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 8.63e-7 AC: 1 AN: 1158272 Hom.: 0 Cov.: 30 AF XY: 0.00000177 AC XY: 1 AN XY: 566024

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

African (AFR) AF: 0.00 AC: 0 AN: 22360

American (AMR) AF: 0.00 AC: 0 AN: 11514

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16114

East Asian (EAS) AF: 0.00 AC: 0 AN: 23864

South Asian (SAS) AF: 0.0000222 AC: 1 AN: 45064

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37016

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3050

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 954510

Other (OTH) AF: 0.00 AC: 0 AN: 44780

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 21

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0084	T
Eigen	Benign	-0.73
Eigen_PC	Benign	-0.69
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.43	T
M_CAP	Benign	0.058	D
MetaRNN	Benign	0.075	T
MetaSVM	Benign	-1.0	T
PhyloP100		1.2
PROVEAN	Benign	0.26	N
REVEL	Benign	0.020
Sift	Benign	0.25	T
Sift4G	Benign	0.34	T
Polyphen		0.0030	B
Vest4		0.12
MutPred		0.19		Loss of methylation at R20 (P = 0.0988)
MVP		0.13
MPC		1.0
ClinPred		0.088	T
GERP RS		2.0
PromoterAI		0.0074	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.085
Mutation Taster		=91/9	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: rs2113088255; hg19: chr5-175665567;