rs45613639

Variant names:

• chr12-88049436-A-G
• rs45613639
• NM_001009894.3:c.*1014A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001009894.3(RLIG1):​c.*1014A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0192 in 1,180,658 control chromosomes in the GnomAD database, including 294 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.016 (27 hom., cov: 32)
  • Exomes 𝑓: 0.020 (267 hom.)
• Consequence: RLIG1 NM_001009894.3 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.04
• Publications: 4 publications found

Genes affected

RLIG1 (HGNC:25322): (RNA 5'-phosphate and 3'-OH ligase 1) Predicted to act upstream of or within hematopoietic progenitor cell differentiation. [provided by Alliance of Genome Resources, Apr 2022]

CEP290 (HGNC:29021): (centrosomal protein 290) This gene encodes a protein with 13 putative coiled-coil domains, a region with homology to SMC chromosome segregation ATPases, six KID motifs, three tropomyosin homology domains and an ATP/GTP binding site motif A. The protein is localized to the centrosome and cilia and has sites for N-glycosylation, tyrosine sulfation, phosphorylation, N-myristoylation, and amidation. Mutations in this gene have been associated with Joubert syndrome and nephronophthisis and the presence of antibodies against this protein is associated with several forms of cancer. [provided by RefSeq, Jul 2008]

CEP290 Gene-Disease associations (from GenCC):

• CEP290-related ciliopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Joubert syndrome 5

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• Bardet-Biedl syndrome 14

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• Leber congenital amaurosis 10

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• Leber congenital amaurosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Bardet-Biedl syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Joubert syndrome with oculorenal defect

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Meckel syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Senior-Loken syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 12-88049436-A-G is Benign according to our data. Variant chr12-88049436-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 126268.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0159 (2414/152132) while in subpopulation EAS AF = 0.0228 (118/5176). AF 95% confidence interval is 0.0203. There are 27 homozygotes in GnomAd4. There are 1197 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 27 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001009894.3. 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
	RLIG1	NM_001009894.3	MANE Select	c.*1014A>G		3_prime_UTR	Exon 7 of 7	NP_001009894.2
	CEP290	NM_025114.4	MANE Select	c.7210-22T>C		intron	N/A	NP_079390.3	O15078

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RLIG1	ENST00000356891.4	TSL:1 MANE Select	c.*1014A>G		3_prime_UTR	Exon 7 of 7	ENSP00000349358.3	Q8N999-1
	CEP290	ENST00000552810.6	TSL:1 MANE Select	c.7210-22T>C		intron	N/A	ENSP00000448012.1	O15078
	CEP290	ENST00000547691.8	TSL:1	c.4177-22T>C		intron	N/A	ENSP00000446905.3	A0A5K1VW81

Frequencies

GnomAD3 genomes AF: 0.0159 AC: 2410 AN: 152014 Hom.: 27 Cov.: 32

Gnomad AFR AF: 0.00722

Gnomad AMI AF: 0.0296

Gnomad AMR AF: 0.0223

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.0227

Gnomad SAS AF: 0.00289

Gnomad FIN AF: 0.0259

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0189

Gnomad OTH AF: 0.0230

GnomAD2 exomes AF: 0.0153 AC: 2037 AN: 132878 AF XY: 0.0150

Gnomad AFR exome AF: 0.00537

Gnomad AMR exome AF: 0.0164

Gnomad ASJ exome AF: 0.00132

Gnomad EAS exome AF: 0.0145

Gnomad FIN exome AF: 0.0253

Gnomad NFE exome AF: 0.0192

Gnomad OTH exome AF: 0.0157

GnomAD4 exome AF: 0.0196 AC: 20199 AN: 1028526 Hom.: 267 Cov.: 14 AF XY: 0.0192 AC XY: 10033 AN XY: 523214

African (AFR) AF: 0.00635 AC: 144 AN: 22664

American (AMR) AF: 0.0161 AC: 388 AN: 24032

Ashkenazi Jewish (ASJ) AF: 0.00135 AC: 29 AN: 21534

East Asian (EAS) AF: 0.0394 AC: 1358 AN: 34470

South Asian (SAS) AF: 0.00353 AC: 231 AN: 65458

European-Finnish (FIN) AF: 0.0237 AC: 1176 AN: 49610

Middle Eastern (MID) AF: 0.00481 AC: 16 AN: 3326

European-Non Finnish (NFE) AF: 0.0211 AC: 16096 AN: 762460

Other (OTH) AF: 0.0169 AC: 761 AN: 44972

GnomAD4 genome AF: 0.0159 AC: 2414 AN: 152132 Hom.: 27 Cov.: 32 AF XY: 0.0161 AC XY: 1197 AN XY: 74362

African (AFR) AF: 0.00729 AC: 303 AN: 41558

American (AMR) AF: 0.0223 AC: 340 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3470

East Asian (EAS) AF: 0.0228 AC: 118 AN: 5176

South Asian (SAS) AF: 0.00290 AC: 14 AN: 4832

European-Finnish (FIN) AF: 0.0259 AC: 275 AN: 10610

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

European-Non Finnish (NFE) AF: 0.0189 AC: 1284 AN: 67894

Other (OTH) AF: 0.0227 AC: 48 AN: 2110

Alfa AF: 0.0149 Hom.: 5

Bravo AF: 0.0143

Asia WGS AF: 0.0110 AC: 37 AN: 3466

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	8.5
DANN	Benign	0.85
PhyloP100		1.0
BranchPoint Hunter		2.0
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: rs45613639; hg19: chr12-88443213;