Genetic Variant SIL1:p.Thr279Lys (chr5-138951816-G-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_022464.5(SIL1):c.836C>A(p.Thr279Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,722 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T279M) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

SIL1
NM_022464.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.91

Publications

3 publications found

Variant links:

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

SIL1 links:

LOC124901079 (HGNC:):

LOC124901079 links:

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ACMG classification

Classification was made for transcript

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.836C>A	p.Thr279Lys	missense	Exon 8 of 10	NP_071909.1	Q9H173
	SIL1	NM_001037633.2		c.836C>A	p.Thr279Lys	missense	Exon 9 of 11	NP_001032722.1	Q9H173

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SIL1	ENST00000394817.7	TSL:1 MANE Select	c.836C>A	p.Thr279Lys	missense	Exon 8 of 10	ENSP00000378294.2	Q9H173
SIL1	ENST00000868003.1		c.968C>A	p.Thr323Lys	missense	Exon 9 of 11	ENSP00000538062.1
SIL1	ENST00000868009.1		c.965C>A	p.Thr322Lys	missense	Exon 9 of 11	ENSP00000538068.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251370

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461722

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727168

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.0000224

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53284

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111982

Other (OTH)

AF:

0.00

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.600

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.49

BayesDel_addAF

Benign

0.0081

BayesDel_noAF

Benign

-0.14

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.37

Eigen

Uncertain

0.52

Eigen_PC

Uncertain

0.52

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.90

M_CAP

Benign

0.011

MetaRNN

Uncertain

0.68

MetaSVM

Benign

-0.90

MutationAssessor

Benign

1.5

PhyloP100

7.9

PrimateAI

Uncertain

0.71

PROVEAN

Uncertain

-2.9

REVEL

Benign

0.21

Sift

Benign

0.081

Sift4G

Uncertain

0.0080

Polyphen

0.99

Vest4

0.63

MutPred

0.45

Gain of ubiquitination at T286 (P = 0.0276)

MVP

0.49

MPC

0.95

ClinPred

0.95

GERP RS

4.8

Varity_R

0.33

gMVP

0.62

Mutation Taster

=67/33

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over