rs751454866

Variant names:

• chr5-138947145-A-G
• rs751454866
• NM_022464.5:c.1358T>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_022464.5(SIL1):​c.1358T>C​(p.Val453Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00000992 in 1,613,420 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: SIL1 NM_022464.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 4.92
• 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: Orphanet, G2P, ClinGen, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16295433).

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.1358T>C	p.Val453Ala	missense	Exon 10 of 10	NP_071909.1	Q9H173
	SIL1	NM_001037633.2		c.1358T>C	p.Val453Ala	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.1358T>C	p.Val453Ala	missense	Exon 10 of 10	ENSP00000378294.2	Q9H173
	SIL1	ENST00000868003.1		c.1490T>C	p.Val497Ala	missense	Exon 11 of 11	ENSP00000538062.1
	SIL1	ENST00000868009.1		c.1487T>C	p.Val496Ala	missense	Exon 11 of 11	ENSP00000538068.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152130 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000160 AC: 4 AN: 250446 AF XY: 0.00000738

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000103 AC: 15 AN: 1461290 Hom.: 0 Cov.: 31 AF XY: 0.0000110 AC XY: 8 AN XY: 726940

African (AFR) AF: 0.000119 AC: 4 AN: 33480

American (AMR) AF: 0.000112 AC: 5 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53086

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1111800

Other (OTH) AF: 0.0000166 AC: 1 AN: 60366

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152130 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74316

African (AFR) AF: 0.00 AC: 0 AN: 41416

American (AMR) AF: 0.0000654 AC: 1 AN: 15284

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68010

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.0000264

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.32	T
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.52
FATHMM_MKL	Benign	0.65	D
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.060	D
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	1.2	L
PhyloP100		4.9
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.14
Sift	Uncertain	0.011	D
Sift4G	Uncertain	0.017	D
Polyphen		0.073	B
Vest4		0.42
MutPred		0.37		Gain of helix (P = 0.0199)
MVP		0.48
MPC		0.34
ClinPred		0.37	T
GERP RS		2.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.063
gMVP		0.25
Mutation Taster		=73/27	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: rs751454866; hg19: chr5-138282834;