NM_022464.5:c.368C>T

Variant names:

• chr5-139042705-G-A
• rs115800498
• NM_022464.5:c.368C>T

Variant summary

Our verdict is Benign. The variant received -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. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T123T) has been classified 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
• Publications: 12 publications found

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 Gene-Disease associations (from GenCC):

• Marinesco-Sjogren syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, G2P, Orphanet, Labcorp Genetics (formerly Invitae)

ENSG00000249593 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 96086.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022464.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SIL1	NM_022464.5	MANE Select	c.368C>T	p.Thr123Ile	missense	Exon 5 of 10	NP_071909.1
	SIL1	NM_001037633.2		c.368C>T	p.Thr123Ile	missense	Exon 6 of 11	NP_001032722.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SIL1	ENST00000394817.7	TSL:1 MANE Select	c.368C>T	p.Thr123Ile	missense	Exon 5 of 10	ENSP00000378294.2
	SIL1	ENST00000868003.1		c.368C>T	p.Thr123Ile	missense	Exon 5 of 11	ENSP00000538062.1
	SIL1	ENST00000868009.1		c.365C>T	p.Thr122Ile	missense	Exon 5 of 11	ENSP00000538068.1

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

GnomAD2 exomes AF: 0.00546 AC: 1374 AN: 251448 AF XY: 0.00568

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 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

African (AFR) AF: 0.00111 AC: 37 AN: 33480

American (AMR) AF: 0.00183 AC: 82 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00134 AC: 35 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.00533 AC: 460 AN: 86256

European-Finnish (FIN) AF: 0.00185 AC: 99 AN: 53418

Middle Eastern (MID) AF: 0.00520 AC: 30 AN: 5768

European-Non Finnish (NFE) AF: 0.00857 AC: 9528 AN: 1111912

Other (OTH) AF: 0.00652 AC: 394 AN: 60394

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

African (AFR) AF: 0.00135 AC: 56 AN: 41542

American (AMR) AF: 0.00294 AC: 45 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5186

South Asian (SAS) AF: 0.00499 AC: 24 AN: 4812

European-Finnish (FIN) AF: 0.000566 AC: 6 AN: 10606

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00840 AC: 571 AN: 68010

Other (OTH) AF: 0.00662 AC: 14 AN: 2116

Alfa AF: 0.00485 Hom.: 14

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

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	3	not specified (3)
-	-	2	Marinesco-Sjögren syndrome (2)
-	-	1	SIL1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.087
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.0062	T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	1.6	L
PhyloP100		1.6
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.25
Sift	Benign	0.032	D
Sift4G	Uncertain	0.016	D
Polyphen		0.22	B
Vest4		0.28
MVP		0.47
MPC		0.37
ClinPred		0.015	T
GERP RS		3.2
PromoterAI		0.029	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.070
gMVP		0.28
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs115800498; hg19: chr5-138378394;