5-138951165-A-G

Variant names:

• chr5-138951165-A-G
• rs57028146
• NM_022464.5:c.1029+6T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_022464.5(SIL1):​c.1029+6T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00436 in 1,610,568 control chromosomes in the GnomAD database, including 255 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.023 (122 hom., cov: 33)
  • Exomes 𝑓: 0.0024 (133 hom.)
• Consequence: SIL1 NM_022464.5 splice_region, intron
• Scores: Splicing: ADA: 0.005142
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.114
• 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)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 5-138951165-A-G is Benign according to our data. Variant chr5-138951165-A-G is described in ClinVar as Benign. ClinVar VariationId is 286857.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.079 is higher than 0.05.

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.1029+6T>C		splice_region intron	N/A	NP_071909.1
	SIL1	NM_001037633.2		c.1029+6T>C		splice_region intron	N/A	NP_001032722.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SIL1	ENST00000394817.7	TSL:1 MANE Select	c.1029+6T>C		splice_region intron	N/A	ENSP00000378294.2
	SIL1	ENST00000509534.5	TSL:5	c.1050+6T>C		splice_region intron	N/A	ENSP00000426858.1
	SIL1	ENST00000265195.9	TSL:5	c.1029+6T>C		splice_region intron	N/A	ENSP00000265195.5

Frequencies

GnomAD3 genomes AF: 0.0233 AC: 3548 AN: 152048 Hom.: 121 Cov.: 33

Gnomad AFR AF: 0.0811

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00871

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000830

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.0163

GnomAD2 exomes AF: 0.00577 AC: 1400 AN: 242762 AF XY: 0.00424

Gnomad AFR exome AF: 0.0790

Gnomad AMR exome AF: 0.00437

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000137

Gnomad OTH exome AF: 0.00302

GnomAD4 exome AF: 0.00238 AC: 3465 AN: 1458402 Hom.: 133 Cov.: 32 AF XY: 0.00206 AC XY: 1490 AN XY: 725052

African (AFR) AF: 0.0801 AC: 2676 AN: 33408

American (AMR) AF: 0.00495 AC: 220 AN: 44462

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26072

East Asian (EAS) AF: 0.00 AC: 0 AN: 39628

South Asian (SAS) AF: 0.000317 AC: 27 AN: 85280

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53036

Middle Eastern (MID) AF: 0.00330 AC: 19 AN: 5764

European-Non Finnish (NFE) AF: 0.000104 AC: 115 AN: 1110498

Other (OTH) AF: 0.00677 AC: 408 AN: 60254

GnomAD4 genome AF: 0.0234 AC: 3561 AN: 152166 Hom.: 122 Cov.: 33 AF XY: 0.0220 AC XY: 1636 AN XY: 74404

African (AFR) AF: 0.0812 AC: 3373 AN: 41516

American (AMR) AF: 0.00863 AC: 132 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.000623 AC: 3 AN: 4814

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

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

European-Non Finnish (NFE) AF: 0.000265 AC: 18 AN: 67990

Other (OTH) AF: 0.0161 AC: 34 AN: 2114

Alfa AF: 0.0144 Hom.: 31

Bravo AF: 0.0263

Asia WGS AF: 0.00664 AC: 24 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Marinesco-Sjögren syndrome (2)
-	-	2	not specified (2)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	6.6
DANN	Benign	0.33
PhyloP100		-0.11
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0051
dbscSNV1_RF	Benign	0.080
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: rs57028146; hg19: chr5-138286854;