chr5-138946768-A-G

Variant names:

• chr5-138946768-A-G
• rs147897662
• NM_022464.5:c.*349T>C

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BS1_Supporting

The NM_022464.5(SIL1):​c.*349T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00105 in 325,160 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0019 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00027 (0 hom.)
• Consequence: SIL1 NM_022464.5 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.47
• 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, PanelApp Australia, G2P, Labcorp Genetics (formerly Invitae), ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00194 (295/152274) while in subpopulation AFR AF = 0.00674 (280/41556). AF 95% confidence interval is 0.00609. There are 0 homozygotes in GnomAd4. There are 138 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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.*349T>C		3_prime_UTR	Exon 10 of 10	NP_071909.1	Q9H173
	SIL1	NM_001037633.2		c.*349T>C		3_prime_UTR	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.*349T>C		3_prime_UTR	Exon 10 of 10	ENSP00000378294.2	Q9H173
	SIL1	ENST00000265195.9	TSL:5	c.*349T>C		3_prime_UTR	Exon 11 of 11	ENSP00000265195.5	Q9H173
	SIL1	ENST00000948133.1		c.*349T>C		3_prime_UTR	Exon 12 of 12	ENSP00000618192.1

Frequencies

GnomAD3 genomes AF: 0.00190 AC: 289 AN: 152156 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00661

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00192

GnomAD4 exome AF: 0.000272 AC: 47 AN: 172886 Hom.: 0 Cov.: 0 AF XY: 0.000133 AC XY: 12 AN XY: 90276

African (AFR) AF: 0.00604 AC: 36 AN: 5960

American (AMR) AF: 0.000602 AC: 5 AN: 8306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 4904

East Asian (EAS) AF: 0.00 AC: 0 AN: 9386

South Asian (SAS) AF: 0.00 AC: 0 AN: 22980

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8740

Middle Eastern (MID) AF: 0.00138 AC: 1 AN: 726

European-Non Finnish (NFE) AF: 0.0000196 AC: 2 AN: 102242

Other (OTH) AF: 0.000311 AC: 3 AN: 9642

GnomAD4 genome AF: 0.00194 AC: 295 AN: 152274 Hom.: 0 Cov.: 33 AF XY: 0.00185 AC XY: 138 AN XY: 74440

African (AFR) AF: 0.00674 AC: 280 AN: 41556

American (AMR) AF: 0.000653 AC: 10 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68014

Other (OTH) AF: 0.00190 AC: 4 AN: 2110

Alfa AF: 0.00160 Hom.: 0

Bravo AF: 0.00211

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

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
BayesDel_noAF	Benign	-0.80
CADD	Benign	5.0
DANN	Benign	0.70
PhyloP100		1.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs147897662; hg19: chr5-138282457;