5-176313811-G-A

Variant names:

• chr5-176313811-G-A
• rs143105269
• NM_001308195.2:c.1855G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001308195.2(SIMC1):​c.1855G>A​(p.Val619Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000641 in 1,613,806 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00030 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00068 (0 hom.)
• Consequence: SIMC1 NM_001308195.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.62
• Publications: 2 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 -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.06586048).

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.1855G>A	p.Val619Met	missense	Exon 5 of 10	NP_001295124.1	Q8NDZ2-5
	SIMC1	NM_001308196.2		c.1798G>A	p.Val600Met	missense	Exon 7 of 12	NP_001295125.1	Q8NDZ2-1
	SIMC1	NM_198567.6		c.553G>A	p.Val185Met	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.1855G>A	p.Val619Met	missense	Exon 5 of 10	ENSP00000410552.3	Q8NDZ2-5
	SIMC1	ENST00000443967.5	TSL:1	c.1798G>A	p.Val600Met	missense	Exon 7 of 12	ENSP00000406571.1	Q8NDZ2-1
	SIMC1	ENST00000332772.4	TSL:1	c.181G>A	p.Val61Met	missense	Exon 2 of 7	ENSP00000331311.4	Q8NDZ2-4

Frequencies

GnomAD3 genomes AF: 0.000302 AC: 46 AN: 152166 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000410

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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: 0.000412

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000171 AC: 43 AN: 250798 AF XY: 0.000170

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000345

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000677 AC: 989 AN: 1461522 Hom.: 0 Cov.: 31 AF XY: 0.000656 AC XY: 477 AN XY: 727046

African (AFR) AF: 0.0000299 AC: 1 AN: 33468

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53396

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5646

European-Non Finnish (NFE) AF: 0.000877 AC: 975 AN: 1111852

Other (OTH) AF: 0.000199 AC: 12 AN: 60354

GnomAD4 genome AF: 0.000302 AC: 46 AN: 152284 Hom.: 1 Cov.: 32 AF XY: 0.000309 AC XY: 23 AN XY: 74462

African (AFR) AF: 0.000409 AC: 17 AN: 41564

American (AMR) AF: 0.0000653 AC: 1 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000412 AC: 28 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000433 Hom.: 0

Bravo AF: 0.000298

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000206 AC: 25

EpiCase AF: 0.000164

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	0.26
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.037	T
Eigen	Benign	-0.13
Eigen_PC	Benign	-0.012
FATHMM_MKL	Benign	0.60	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.066	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.69	N
PhyloP100		2.6
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-0.80	N
REVEL	Benign	0.081
Sift	Benign	0.19	T
Sift4G	Benign	0.62	T
Polyphen		0.094	B
Vest4		0.33
MVP		0.63
MPC		0.082
ClinPred		0.031	T
GERP RS		3.4
Varity_R		0.044
gMVP		0.33
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: rs143105269; hg19: chr5-175740814;