rs115800498

Positions:

• chr5-139042705-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_022464.5(SIL1):​c.368C>T​(p.Thr123Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00705 in 1,614,034 control chromosomes in the GnomAD database, including 65 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0047 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0073 (60 hom.)
• Consequence: SIL1 NM_022464.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 1.61

Genes affected

SIL1 (HGNC:24624): (SIL1 nucleotide exchange factor) This gene encodes a resident endoplasmic reticulum (ER), N-linked glycoprotein with an N-terminal ER targeting sequence, 2 putative N-glycosylation sites, and a C-terminal ER retention signal. This protein functions as a nucleotide exchange factor for another unfolded protein response protein. Mutations in this gene have been associated with Marinesco-Sjogren syndrome. Alternate transcriptional splice variants have been characterized. [provided by RefSeq, Jul 2008]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0076738596).
• BP6: Variant 5-139042705-G-A is Benign according to our data. Variant chr5-139042705-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 96086.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-139042705-G-A is described in Lovd as [Benign]. Variant chr5-139042705-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00472 (719/152248) while in subpopulation NFE AF= 0.0084 (571/68010). AF 95% confidence interval is 0.00783. There are 5 homozygotes in gnomad4. There are 339 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SIL1	NM_022464.5	c.368C>T	p.Thr123Ile	missense_variant	5/10	ENST00000394817.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SIL1	ENST00000394817.7	c.368C>T	p.Thr123Ile	missense_variant	5/10	1	NM_022464.5	P1
	ENST00000512875.2	n.529+8263G>A		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.00473 AC: 719 AN: 152130 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.00135

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00295

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00498

Gnomad FIN AF: 0.000566

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00839

Gnomad OTH AF: 0.00669

GnomAD3 exomes AF: 0.00546 AC: 1374 AN: 251448 Hom.: 7 AF XY: 0.00568 AC XY: 772 AN XY: 135884

Gnomad AFR exome AF: 0.00203

Gnomad AMR exome AF: 0.00173

Gnomad ASJ exome AF: 0.000992

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00559

Gnomad FIN exome AF: 0.00143

Gnomad NFE exome AF: 0.00898

Gnomad OTH exome AF: 0.00782

GnomAD4 exome AF: 0.00730 AC: 10666 AN: 1461786 Hom.: 60 Cov.: 31 AF XY: 0.00720 AC XY: 5235 AN XY: 727186

Gnomad4 AFR exome AF: 0.00111

Gnomad4 AMR exome AF: 0.00183

Gnomad4 ASJ exome AF: 0.00134

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00533

Gnomad4 FIN exome AF: 0.00185

Gnomad4 NFE exome AF: 0.00857

Gnomad4 OTH exome AF: 0.00652

GnomAD4 genome AF: 0.00472 AC: 719 AN: 152248 Hom.: 5 Cov.: 32 AF XY: 0.00455 AC XY: 339 AN XY: 74432

Gnomad4 AFR AF: 0.00135

Gnomad4 AMR AF: 0.00294

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00499

Gnomad4 FIN AF: 0.000566

Gnomad4 NFE AF: 0.00840

Gnomad4 OTH AF: 0.00662

Alfa AF: 0.00730 Hom.: 9

Bravo AF: 0.00493

TwinsUK AF: 0.0108 AC: 40

ALSPAC AF: 0.00830 AC: 32

ESP6500AA AF: 0.00340 AC: 15

ESP6500EA AF: 0.00779 AC: 67

ExAC AF: 0.00576 AC: 699

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00807

EpiControl AF: 0.00776

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 01, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	SIL1: BP4, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 07, 2016	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

not specified Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Mar 02, 2021	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 01, 2013	- -

Marinesco-Sjögren syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

SIL1-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 08, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.24	T;T;.;T;T
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.087
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.81	.;T;T;T;T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.0062	T;T;T;T;T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	1.6	L;L;.;.;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-2.1	N;N;N;N;N
REVEL	Benign	0.25
Sift	Benign	0.032	D;D;D;D;D
Sift4G	Uncertain	0.016	D;D;D;D;.
Polyphen		0.22	B;B;B;.;.
Vest4		0.28
MVP		0.47
MPC		0.37
ClinPred		0.015	T
GERP RS		3.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.070
gMVP		0.28

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

LitVar

Other links and lift over

dbSNP: rs115800498; hg19: chr5-138378394;