rs11555154

chr5-139127849-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_022464.5(SIL1):c.-6C>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.075 in 1,584,276 control chromosomes in the GnomAD database, including 5,027 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.060 (383 hom., cov: 31)
  • Exomes 𝑓: 0.077 (4644 hom.)
• Consequence: SIL1 NM_022464.5 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.109

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017609298).
• BP6: Variant 5-139127849-G-C is Benign according to our data. Variant chr5-139127849-G-C is described in ClinVar as [Benign]. Clinvar id is 261600.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-139127849-G-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0814 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SIL1	NM_022464.5	c.-6C>G		5_prime_UTR_variant	2/10	ENST00000394817.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SIL1	ENST00000394817.7	c.-6C>G		5_prime_UTR_variant	2/10	1	NM_022464.5	P1

Frequencies

GnomAD3 genomes AF: 0.0601 AC: 9114 AN: 151548 Hom.: 381 Cov.: 31

Gnomad AFR AF: 0.0185

Gnomad AMI AF: 0.0351

Gnomad AMR AF: 0.0695

Gnomad ASJ AF: 0.102

Gnomad EAS AF: 0.00405

Gnomad SAS AF: 0.0190

Gnomad FIN AF: 0.0917

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.0832

Gnomad OTH AF: 0.0804

GnomAD3 exomes AF: 0.0657 AC: 14001 AN: 213060 Hom.: 564 AF XY: 0.0660 AC XY: 7561 AN XY: 114486

Gnomad AFR exome AF: 0.0176

Gnomad AMR exome AF: 0.0496

Gnomad ASJ exome AF: 0.0987

Gnomad EAS exome AF: 0.00119

Gnomad SAS exome AF: 0.0198

Gnomad FIN exome AF: 0.0943

Gnomad NFE exome AF: 0.0924

Gnomad OTH exome AF: 0.0705

GnomAD4 exome AF: 0.0766 AC: 109680 AN: 1432610 Hom.: 4644 Cov.: 28 AF XY: 0.0754 AC XY: 53647 AN XY: 711402

Gnomad4 AFR exome AF: 0.0184

Gnomad4 AMR exome AF: 0.0503

Gnomad4 ASJ exome AF: 0.0979

Gnomad4 EAS exome AF: 0.0111

Gnomad4 SAS exome AF: 0.0204

Gnomad4 FIN exome AF: 0.0903

Gnomad4 NFE exome AF: 0.0850

Gnomad4 OTH exome AF: 0.0730

GnomAD4 genome AF: 0.0601 AC: 9120 AN: 151666 Hom.: 383 Cov.: 31 AF XY: 0.0604 AC XY: 4477 AN XY: 74068

Gnomad4 AFR AF: 0.0184

Gnomad4 AMR AF: 0.0695

Gnomad4 ASJ AF: 0.102

Gnomad4 EAS AF: 0.00406

Gnomad4 SAS AF: 0.0194

Gnomad4 FIN AF: 0.0917

Gnomad4 NFE AF: 0.0832

Gnomad4 OTH AF: 0.0824

Alfa AF: 0.0790 Hom.: 179

Bravo AF: 0.0573

TwinsUK AF: 0.0804 AC: 298

ALSPAC AF: 0.0765 AC: 295

ESP6500AA AF: 0.0211 AC: 93

ESP6500EA AF: 0.0794 AC: 683

ExAC AF: 0.0607 AC: 7344

Asia WGS AF: 0.0190 AC: 67 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

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	GeneDx	Feb 04, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Marinesco-Sjögren syndrome Benign:1

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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.40
Cadd	Benign	1.2
Dann	Uncertain	0.99
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.74
FATHMM_MKL	Benign	0.024	N
LIST_S2	Benign	0.34	T;T;T
MetaRNN	Benign	0.0018	T;T;T
MetaSVM	Benign	-0.86	T
MutationTaster	Benign	1.0	P;P;P
PROVEAN	Benign	0.010	N;N;N
REVEL	Benign	0.024
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;.
Vest4		0.053
ClinPred		0.0093	T
GERP RS		1.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs11555154; hg19: chr5-138463538; COSMIC: COSV54533653;