5-139121126-T-C

Position:

• chr5-139121126-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_022464.5(SIL1):​c.153A>G​(p.Thr51=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.439 in 1,613,918 control chromosomes in the GnomAD database, including 160,014 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.49 (19435 hom., cov: 32)
  • Exomes 𝑓: 0.43 (140579 hom.)
• Consequence: SIL1 NM_022464.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.964

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 5-139121126-T-C is Benign according to our data. Variant chr5-139121126-T-C is described in ClinVar as [Benign]. Clinvar id is 96085.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-139121126-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.964 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.662 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SIL1	NM_022464.5	c.153A>G	p.Thr51=	synonymous_variant	3/10	ENST00000394817.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SIL1	ENST00000394817.7	c.153A>G	p.Thr51=	synonymous_variant	3/10	1	NM_022464.5	P1

Frequencies

GnomAD3 genomes AF: 0.491 AC: 74610 AN: 151980 Hom.: 19397 Cov.: 32

Gnomad AFR AF: 0.668

Gnomad AMI AF: 0.353

Gnomad AMR AF: 0.411

Gnomad ASJ AF: 0.493

Gnomad EAS AF: 0.169

Gnomad SAS AF: 0.373

Gnomad FIN AF: 0.454

Gnomad MID AF: 0.497

Gnomad NFE AF: 0.442

Gnomad OTH AF: 0.475

GnomAD3 exomes AF: 0.427 AC: 107454 AN: 251432 Hom.: 24274 AF XY: 0.423 AC XY: 57456 AN XY: 135896

Gnomad AFR exome AF: 0.672

Gnomad AMR exome AF: 0.401

Gnomad ASJ exome AF: 0.482

Gnomad EAS exome AF: 0.167

Gnomad SAS exome AF: 0.387

Gnomad FIN exome AF: 0.461

Gnomad NFE exome AF: 0.442

Gnomad OTH exome AF: 0.433

GnomAD4 exome AF: 0.434 AC: 634266 AN: 1461818 Hom.: 140579 Cov.: 56 AF XY: 0.433 AC XY: 315159 AN XY: 727210

Gnomad4 AFR exome AF: 0.678

Gnomad4 AMR exome AF: 0.401

Gnomad4 ASJ exome AF: 0.487

Gnomad4 EAS exome AF: 0.194

Gnomad4 SAS exome AF: 0.388

Gnomad4 FIN exome AF: 0.462

Gnomad4 NFE exome AF: 0.437

Gnomad4 OTH exome AF: 0.439

GnomAD4 genome AF: 0.491 AC: 74699 AN: 152100 Hom.: 19435 Cov.: 32 AF XY: 0.485 AC XY: 36089 AN XY: 74348

Gnomad4 AFR AF: 0.668

Gnomad4 AMR AF: 0.410

Gnomad4 ASJ AF: 0.493

Gnomad4 EAS AF: 0.169

Gnomad4 SAS AF: 0.372

Gnomad4 FIN AF: 0.454

Gnomad4 NFE AF: 0.442

Gnomad4 OTH AF: 0.474

Alfa AF: 0.474 Hom.: 9757

Bravo AF: 0.494

Asia WGS AF: 0.304 AC: 1055 AN: 3478

EpiCase AF: 0.439

EpiControl AF: 0.433

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 27, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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	Jan 05, 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. -

Marinesco-Sjögren syndrome Benign:5

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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. -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Apr 14, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.65
DANN	Benign	0.39

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs3088052; hg19: chr5-138456815; COSMIC: COSV54530288;