NM_022464.5:c.1330G>T

Variant names:

• chr5-138947173-C-A
• NM_022464.5:c.1330G>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_022464.5(SIL1):​c.1330G>T​(p.Gly444Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G444V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SIL1 NM_022464.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.37
• 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, G2P, ClinGen, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.1330G>T	p.Gly444Cys	missense	Exon 10 of 10	NP_071909.1	Q9H173
	SIL1	NM_001037633.2		c.1330G>T	p.Gly444Cys	missense	Exon 11 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.1330G>T	p.Gly444Cys	missense	Exon 10 of 10	ENSP00000378294.2	Q9H173
	SIL1	ENST00000868003.1		c.1462G>T	p.Gly488Cys	missense	Exon 11 of 11	ENSP00000538062.1
	SIL1	ENST00000868009.1		c.1459G>T	p.Gly487Cys	missense	Exon 11 of 11	ENSP00000538068.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Marinesco-Sjögren syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.44
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.0
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.65	D
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.82	T
M_CAP	Uncertain	0.13	D
MetaRNN	Uncertain	0.65	D
MetaSVM	Uncertain	0.057	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		2.4
PrimateAI	Uncertain	0.48	T
PROVEAN	Uncertain	-3.3	D
REVEL	Uncertain	0.47
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.016	D
Polyphen		1.0	D
Vest4		0.56
MutPred		0.32		Loss of disorder (P = 0.0157)
MVP		0.72
MPC		0.89
ClinPred		0.96	D
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.44
gMVP		0.28
Mutation Taster		=47/53	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

hg19: chr5-138282862;