5-138947152-C-T

Position:

chr5-138947152-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM2BP4_StrongBP6_Very_StrongBS1

The ENST00000394817.7(SIL1):c.1351G>A(p.Gly451Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000404 in 1,613,654 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00023 ( 0 hom. )

Consequence

SIL1
ENST00000394817.7 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 1.10

Variant links:

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]

SIL1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.0061315).

BP6

Variant 5-138947152-C-T is Benign according to our data. Variant chr5-138947152-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 286537.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-138947152-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00203 (309/152314) while in subpopulation AFR AF= 0.00712 (296/41568). AF 95% confidence interval is 0.00645. There are 0 homozygotes in gnomad4. There are 144 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SIL1	NM_022464.5 linkuse as main transcript	c.1351G>A	p.Gly451Ser	missense_variant	10/10	ENST00000394817.7	NP_071909.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
SIL1	ENST00000394817.7 linkuse as main transcript	c.1351G>A	p.Gly451Ser	missense_variant	10/10	1	NM_022464.5	ENSP00000378294	P1
SIL1	ENST00000509534.5 linkuse as main transcript	c.1372G>A	p.Gly458Ser	missense_variant	11/11	5		ENSP00000426858
SIL1	ENST00000265195.9 linkuse as main transcript	c.1351G>A	p.Gly451Ser	missense_variant	11/11	5		ENSP00000265195	P1
SIL1	ENST00000515008.1 linkuse as main transcript	n.686G>A		non_coding_transcript_exon_variant	4/4	3

Frequencies

GnomAD3 genomes

AF:

0.00202

AC:

308

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00709

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000523

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:

0.0000294

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.000499

AC:

125

AN:

250568

Hom.:

AF XY:

0.000317

AC XY:

AN XY:

135540

show subpopulations

Gnomad AFR exome

AF:

0.00691

Gnomad AMR exome

AF:

0.000174

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000619

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000235

AC:

343

AN:

1461340

Hom.:

Cov.:

AF XY:

0.000202

AC XY:

147

AN XY:

726968

show subpopulations

Gnomad4 AFR exome

AF:

0.00768

Gnomad4 AMR exome

AF:

0.000268

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000333

Gnomad4 OTH exome

AF:

0.000530

GnomAD4 genome

AF:

0.00203

AC:

309

AN:

152314

Hom.:

Cov.:

AF XY:

0.00193

AC XY:

144

AN XY:

74486

show subpopulations

Gnomad4 AFR

AF:

0.00712

Gnomad4 AMR

AF:

0.000457

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.000880

Hom.:

Bravo

AF:

0.00230

ESP6500AA

AF:

0.00613

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000610

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 02, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 13, 2019	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Marinesco-Sjögren syndrome

Benign:2

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. -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Mar 01, 2016

- -

SIL1-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 25, 2019

This variant is classified as likely 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

0.072

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.41

CADD

Benign

DANN

Benign

0.91

DEOGEN2

Benign

0.082

T;T;.

Eigen

Benign

-0.52

Eigen_PC

Benign

-0.31

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.82

.;T;T

M_CAP

Benign

0.015

MetaRNN

Benign

0.0061

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.97

L;L;.

MutationTaster

Benign

0.71

N;N;N

PrimateAI

Benign

0.31

PROVEAN

Benign

0.44

N;N;N

REVEL

Benign

0.12

Sift

Benign

0.50

T;T;T

Sift4G

Benign

0.95

T;T;T

Polyphen

0.0070

B;B;B

Vest4

0.15

MVP

0.43

MPC

0.24

ClinPred

0.0057

GERP RS

4.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.021

gMVP

0.073

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over