rs45613639

chr12-88049436-A-G

Variant summary

Our verdict is Benign. Variant got -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:3
• Conservation: PhyloP100: 1.04

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]

ACMG classification

Verdict is Benign. Variant got -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 id is 126268.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-88049436-A-G is described in Lovd as [Benign].
• 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 27 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RLIG1	NM_001009894.3	c.*1014A>G		3_prime_UTR_variant	7/7	ENST00000356891.4
CEP290	NM_025114.4	c.7210-22T>C		intron_variant		ENST00000552810.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RLIG1	ENST00000356891.4	c.*1014A>G		3_prime_UTR_variant	7/7	1	NM_001009894.3	P1
CEP290	ENST00000552810.6	c.7210-22T>C		intron_variant		1	NM_025114.4	P4

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

GnomAD3 exomes AF: 0.0153 AC: 2037 AN: 132878 Hom.: 24 AF XY: 0.0150 AC XY: 1071 AN XY: 71330

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 SAS exome AF: 0.00302

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

Gnomad4 AFR exome AF: 0.00635

Gnomad4 AMR exome AF: 0.0161

Gnomad4 ASJ exome AF: 0.00135

Gnomad4 EAS exome AF: 0.0394

Gnomad4 SAS exome AF: 0.00353

Gnomad4 FIN exome AF: 0.0237

Gnomad4 NFE exome AF: 0.0211

Gnomad4 OTH exome AF: 0.0169

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

Gnomad4 AFR AF: 0.00729

Gnomad4 AMR AF: 0.0223

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.0228

Gnomad4 SAS AF: 0.00290

Gnomad4 FIN AF: 0.0259

Gnomad4 NFE AF: 0.0189

Gnomad4 OTH AF: 0.0227

Alfa AF: 0.0149 Hom.: 5

Bravo AF: 0.0143

Asia WGS AF: 0.0110 AC: 37 AN: 3466

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 27, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
Cadd	Benign	8.5
Dann	Benign	0.85

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

Publications

LitVar

Other links and lift over

dbSNP: rs45613639; hg19: chr12-88443213;