chr5-139042705-G-T

Variant names:

• chr5-139042705-G-T
• rs115800498
• NM_022464.5:c.368C>A

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.368C>A​(p.Thr123Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,250 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. 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. T123I) has been classified as Likely benign.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: SIL1 NM_022464.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.61
• 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: ClinGen, G2P, Orphanet, Labcorp Genetics (formerly Invitae)

ENSG00000249593 (HGNC:):

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=0.11842793).

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.368C>A	p.Thr123Asn	missense	Exon 5 of 10	NP_071909.1
	SIL1	NM_001037633.2		c.368C>A	p.Thr123Asn	missense	Exon 6 of 11	NP_001032722.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SIL1	ENST00000394817.7	TSL:1 MANE Select	c.368C>A	p.Thr123Asn	missense	Exon 5 of 10	ENSP00000378294.2
	SIL1	ENST00000868003.1		c.368C>A	p.Thr123Asn	missense	Exon 5 of 11	ENSP00000538062.1
	SIL1	ENST00000868009.1		c.365C>A	p.Thr122Asn	missense	Exon 5 of 11	ENSP00000538068.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152132 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

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

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152250 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74432

African (AFR) AF: 0.00 AC: 0 AN: 41542

American (AMR) AF: 0.00 AC: 0 AN: 15302

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

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

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

Other (OTH) AF: 0.00 AC: 0 AN: 2116

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.072	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	18
DANN	Benign	0.92
DEOGEN2	Benign	0.17	T
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.21
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.093	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.2	L
PhyloP100		1.6
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.044
Sift	Benign	0.074	T
Sift4G	Uncertain	0.039	D
Polyphen		0.021	B
Vest4		0.26
MutPred		0.21		Loss of helix (P = 0.0196)
MVP		0.40
MPC		0.35
ClinPred		0.18	T
GERP RS		3.2
PromoterAI		0.016	Neutral
Varity_R		0.072
gMVP		0.30
Mutation Taster		=99/1	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: rs115800498; hg19: chr5-138378394;