5-139127849-G-C

Variant names:

• chr5-139127849-G-C
• rs11555154
• NM_022464.5:c.-6C>G

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.-6C>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.075 in 1,584,276 control chromosomes in the GnomAD database, including 5,027 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.060 (383 hom., cov: 31)
  • Exomes 𝑓: 0.077 (4644 hom.)
• Consequence: SIL1 NM_022464.5 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.109
• Publications: 6 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 (MetaRNN=0.0017609298).
• BP6: Variant 5-139127849-G-C is Benign according to our data. Variant chr5-139127849-G-C is described in ClinVar as Benign. ClinVar VariationId is 261600.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0814 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.-6C>G		5_prime_UTR	Exon 2 of 10	NP_071909.1
	SIL1	NM_001037633.2		c.-6C>G		5_prime_UTR	Exon 3 of 11	NP_001032722.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SIL1	ENST00000394817.7	TSL:1 MANE Select	c.-6C>G		5_prime_UTR	Exon 2 of 10	ENSP00000378294.2
	SIL1	ENST00000509534.5	TSL:5	c.19C>G	p.Leu7Val	missense	Exon 3 of 11	ENSP00000426858.1
	SIL1	ENST00000507002.5	TSL:3	c.25C>G	p.Leu9Val	missense	Exon 4 of 6	ENSP00000421890.1

Frequencies

GnomAD3 genomes AF: 0.0601 AC: 9114 AN: 151548 Hom.: 381 Cov.: 31

Gnomad AFR AF: 0.0185

Gnomad AMI AF: 0.0351

Gnomad AMR AF: 0.0695

Gnomad ASJ AF: 0.102

Gnomad EAS AF: 0.00405

Gnomad SAS AF: 0.0190

Gnomad FIN AF: 0.0917

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.0832

Gnomad OTH AF: 0.0804

GnomAD2 exomes AF: 0.0657 AC: 14001 AN: 213060 AF XY: 0.0660

Gnomad AFR exome AF: 0.0176

Gnomad AMR exome AF: 0.0496

Gnomad ASJ exome AF: 0.0987

Gnomad EAS exome AF: 0.00119

Gnomad FIN exome AF: 0.0943

Gnomad NFE exome AF: 0.0924

Gnomad OTH exome AF: 0.0705

GnomAD4 exome AF: 0.0766 AC: 109680 AN: 1432610 Hom.: 4644 Cov.: 28 AF XY: 0.0754 AC XY: 53647 AN XY: 711402

African (AFR) AF: 0.0184 AC: 606 AN: 32888

American (AMR) AF: 0.0503 AC: 2094 AN: 41612

Ashkenazi Jewish (ASJ) AF: 0.0979 AC: 2514 AN: 25678

East Asian (EAS) AF: 0.0111 AC: 431 AN: 38824

South Asian (SAS) AF: 0.0204 AC: 1694 AN: 82836

European-Finnish (FIN) AF: 0.0903 AC: 4705 AN: 52124

Middle Eastern (MID) AF: 0.0619 AC: 345 AN: 5578

European-Non Finnish (NFE) AF: 0.0850 AC: 92957 AN: 1093732

Other (OTH) AF: 0.0730 AC: 4334 AN: 59338

GnomAD4 genome AF: 0.0601 AC: 9120 AN: 151666 Hom.: 383 Cov.: 31 AF XY: 0.0604 AC XY: 4477 AN XY: 74068

African (AFR) AF: 0.0184 AC: 761 AN: 41364

American (AMR) AF: 0.0695 AC: 1053 AN: 15152

Ashkenazi Jewish (ASJ) AF: 0.102 AC: 353 AN: 3462

East Asian (EAS) AF: 0.00406 AC: 21 AN: 5174

South Asian (SAS) AF: 0.0194 AC: 93 AN: 4790

European-Finnish (FIN) AF: 0.0917 AC: 963 AN: 10500

Middle Eastern (MID) AF: 0.0646 AC: 19 AN: 294

European-Non Finnish (NFE) AF: 0.0832 AC: 5652 AN: 67918

Other (OTH) AF: 0.0824 AC: 173 AN: 2100

Alfa AF: 0.0790 Hom.: 179

Bravo AF: 0.0573

TwinsUK AF: 0.0804 AC: 298

ALSPAC AF: 0.0765 AC: 295

ESP6500AA AF: 0.0211 AC: 93

ESP6500EA AF: 0.0794 AC: 683

ExAC AF: 0.0607 AC: 7344

Asia WGS AF: 0.0190 AC: 67 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	1	Marinesco-Sjögren syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	1.2
DANN	Uncertain	0.99
DEOGEN2	Benign	0.015	T
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.74
FATHMM_MKL	Benign	0.024	N
LIST_S2	Benign	0.34	T
MetaRNN	Benign	0.0018	T
MetaSVM	Benign	-0.86	T
PhyloP100		-0.11
PROVEAN	Benign	0.010	N
REVEL	Benign	0.024
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Vest4		0.053
ClinPred		0.0093	T
GERP RS		1.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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: rs11555154; hg19: chr5-138463538; COSMIC: COSV54533653;