5-139051003-C-G

Variant names:

• chr5-139051003-C-G
• rs368830878
• NM_022464.5:c.288G>C

Variant summary

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

The NM_022464.5(SIL1):​c.288G>C​(p.Gln96His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SIL1 NM_022464.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.565
• Publications: 1 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: 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SIL1	NM_022464.5	MANE Select	c.288G>C	p.Gln96His	missense	Exon 4 of 10	NP_071909.1
	SIL1	NM_001037633.2		c.288G>C	p.Gln96His	missense	Exon 5 of 11	NP_001032722.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SIL1	ENST00000394817.7	TSL:1 MANE Select	c.288G>C	p.Gln96His	missense	Exon 4 of 10	ENSP00000378294.2
	SIL1	ENST00000509534.5	TSL:5	c.309G>C	p.Gln103His	missense	Exon 5 of 11	ENSP00000426858.1
	SIL1	ENST00000265195.9	TSL:5	c.288G>C	p.Gln96His	missense	Exon 5 of 11	ENSP00000265195.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.76	D
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.064	D
MetaRNN	Uncertain	0.44	T
MetaSVM	Uncertain	-0.22	T
MutationAssessor	Benign	2.0	M
PhyloP100		0.56
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-3.2	D
REVEL	Uncertain	0.34
Sift	Uncertain	0.0040	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.57
MutPred		0.37		Gain of methylation at R99 (P = 0.1117)
MVP		0.64
MPC		0.84
ClinPred		0.97	D
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.45
gMVP		0.48
Mutation Taster		=54/46	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs368830878; hg19: chr5-138386692;