rs119456967

chr5-138947133-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP5

The NM_022464.5(SIL1):c.1370T>C(p.Leu457Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,058 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: SIL1 NM_022464.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 3.65

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-138947133-A-G is Pathogenic according to our data. Variant chr5-138947133-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 2628.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SIL1	NM_022464.5	c.1370T>C	p.Leu457Pro	missense_variant	10/10	ENST00000394817.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SIL1	ENST00000394817.7	c.1370T>C	p.Leu457Pro	missense_variant	10/10	1	NM_022464.5	P1
SIL1	ENST00000509534.5	c.1391T>C	p.Leu464Pro	missense_variant	11/11	5
SIL1	ENST00000265195.9	c.1370T>C	p.Leu457Pro	missense_variant	11/11	5		P1
SIL1	ENST00000515008.1	n.705T>C		non_coding_transcript_exon_variant	4/4	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000400 AC: 1 AN: 249886 Hom.: 0 AF XY: 0.00000739 AC XY: 1 AN XY: 135228

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461058 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 726812

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Marinesco-Sjögren syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Aug 01, 2008

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.62
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	0.090
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Benign	0.41	T;T;.
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Uncertain	0.097	D
MetaRNN	Uncertain	0.71	D;D;D
MetaSVM	Benign	-0.42	T
MutationAssessor	Benign	1.8	L;L;.
MutationTaster	Benign	1.0	A;A;A
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-2.2	N;N;N
REVEL	Uncertain	0.58
Sift	Uncertain	0.012	D;D;D
Sift4G	Benign	0.099	T;T;T
Polyphen		0.95	P;P;P
Vest4		0.59
MutPred		0.62		.;.;Loss of stability (P = 0.0178);
MVP		0.71
MPC		0.78
ClinPred		0.78	D
GERP RS		4.1
Varity_R		0.63
gMVP		0.63

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: rs119456967; hg19: chr5-138282822;