5-138947152-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM2 BP4_Strong BP6_Very_Strong BS1

The NM_022464.5(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 NM_022464.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.10

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 -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	UniProt
SIL1	NM_022464.5	c.1351G>A	p.Gly451Ser	missense_variant	10/10	ENST00000394817.7

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.00202 AC: 308 AN: 152196 Hom.: 0 Cov.: 33

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.: 0 AF XY: 0.000317 AC XY: 43 AN XY: 135540

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.: 0 Cov.: 31 AF XY: 0.000202 AC XY: 147 AN XY: 726968

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.: 0 Cov.: 33 AF XY: 0.00193 AC XY: 144 AN XY: 74486

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.: 0

Bravo AF: 0.00230

ESP6500AA AF: 0.00613 AC: 27

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000610 AC: 74

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Marinesco-Sjögren syndrome Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 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. -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 02, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 13, 2019	- -

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, criteria provided, single submitter

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	T
BayesDel_noAF	Benign	-0.41
Cadd	Benign	16
Dann	Benign	0.91
DEOGEN2	Benign	0.082	T;T;.
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.31
FATHMM_MKL	Uncertain	0.85	D
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.0061	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.97	L;L;.
MutationTaster	Benign	0.71	N;N;N
PrimateAI	Benign	0.31	T
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	T
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

Other links and lift over

dbSNP: rs34214251; hg19: chr5-138282841;