rs368666457

Variant names:

• chr5-138951216-G-A
• rs368666457
• NM_022464.5:c.984C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Moderate BP6 BP7

The NM_022464.5(SIL1):​c.984C>T​(p.Leu328Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000277 in 1,608,820 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00028 (0 hom.)
• Consequence: SIL1 NM_022464.5 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 0.330
• Publications: 0 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: Orphanet, PanelApp Australia, G2P, Labcorp Genetics (formerly Invitae), ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BP6: Variant 5-138951216-G-A is Benign according to our data. Variant chr5-138951216-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 199168.
• BP7: Synonymous conserved (PhyloP=0.33 with no splicing effect.

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.984C>T	p.Leu328Leu	synonymous	Exon 9 of 10	NP_071909.1	Q9H173
	SIL1	NM_001037633.2		c.984C>T	p.Leu328Leu	synonymous	Exon 10 of 11	NP_001032722.1	Q9H173

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SIL1	ENST00000394817.7	TSL:1 MANE Select	c.984C>T	p.Leu328Leu	synonymous	Exon 9 of 10	ENSP00000378294.2	Q9H173
	SIL1	ENST00000868003.1		c.1116C>T	p.Leu372Leu	synonymous	Exon 10 of 11	ENSP00000538062.1
	SIL1	ENST00000868009.1		c.1113C>T	p.Leu371Leu	synonymous	Exon 10 of 11	ENSP00000538068.1

Frequencies

GnomAD3 genomes AF: 0.000263 AC: 40 AN: 152212 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000485

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000273 AC: 65 AN: 238252 AF XY: 0.000310

Gnomad AFR exome AF: 0.0000671

Gnomad AMR exome AF: 0.000148

Gnomad ASJ exome AF: 0.000102

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000438

Gnomad OTH exome AF: 0.000343

GnomAD4 exome AF: 0.000279 AC: 406 AN: 1456608 Hom.: 0 Cov.: 32 AF XY: 0.000298 AC XY: 216 AN XY: 723954

African (AFR) AF: 0.0000300 AC: 1 AN: 33374

American (AMR) AF: 0.000158 AC: 7 AN: 44318

Ashkenazi Jewish (ASJ) AF: 0.0000384 AC: 1 AN: 26016

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39496

South Asian (SAS) AF: 0.000518 AC: 44 AN: 84972

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52850

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5762

European-Non Finnish (NFE) AF: 0.000296 AC: 329 AN: 1109624

Other (OTH) AF: 0.000282 AC: 17 AN: 60196

GnomAD4 genome AF: 0.000263 AC: 40 AN: 152212 Hom.: 0 Cov.: 33 AF XY: 0.000242 AC XY: 18 AN XY: 74344

African (AFR) AF: 0.0000724 AC: 3 AN: 41458

American (AMR) AF: 0.000131 AC: 2 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000485 AC: 33 AN: 68040

Other (OTH) AF: 0.000478 AC: 1 AN: 2094

Alfa AF: 0.000444 Hom.: 0

Bravo AF: 0.000295

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (2)
-	-	1	Marinesco-Sjögren syndrome (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
CADD	Benign	9.9
DANN	Benign	0.40
PhyloP100		0.33
Mutation Taster		=30/70	disease causing

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: rs368666457; hg19: chr5-138286905;