3-150927621-G-A

Position:

• chr3-150927621-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000327047.6(CLRN1):​c.*315C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.709 in 514,546 control chromosomes in the GnomAD database, including 131,785 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.76 (44699 hom., cov: 29)
  • Exomes 𝑓: 0.69 (87086 hom.)
• Consequence: CLRN1 ENST00000327047.6 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.0100

Genes affected

CLRN1 (HGNC:12605): (clarin 1) This gene encodes a protein that contains a cytosolic N-terminus, multiple helical transmembrane domains, and an endoplasmic reticulum membrane retention signal, TKGH, in the C-terminus. The encoded protein may be important in development and homeostasis of the inner ear and retina. Mutations within this gene have been associated with Usher syndrome type IIIa. Multiple transcript variants encoding distinct isoforms have been identified for this gene. [provided by RefSeq, Jul 2008]

(HGNC:):

CLRN1-AS1 (HGNC:30895): (CLRN1 antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 3-150927621-G-A is Benign according to our data. Variant chr3-150927621-G-A is described in ClinVar as [Benign]. Clinvar id is 343805.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.915 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLRN1	NM_174878.3	c.*315C>T		3_prime_UTR_variant	3/3	ENST00000327047.6	NP_777367.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLRN1	ENST00000327047.6	c.*315C>T		3_prime_UTR_variant	3/3	1	NM_174878.3	ENSP00000322280	P1
CLRN1	ENST00000295911.6	c.342+444C>T		intron_variant		1		ENSP00000295911
	ENST00000469268.1	n.235+36751G>A		intron_variant, non_coding_transcript_variant		4
CLRN1-AS1	ENST00000476886.5	n.123+75015G>A		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.760 AC: 115213 AN: 151544 Hom.: 44659 Cov.: 29

Gnomad AFR AF: 0.923

Gnomad AMI AF: 0.760

Gnomad AMR AF: 0.706

Gnomad ASJ AF: 0.553

Gnomad EAS AF: 0.805

Gnomad SAS AF: 0.629

Gnomad FIN AF: 0.677

Gnomad MID AF: 0.636

Gnomad NFE AF: 0.704

Gnomad OTH AF: 0.729

GnomAD3 exomes AF: 0.692 AC: 89543 AN: 129488 Hom.: 31454 AF XY: 0.685 AC XY: 48271 AN XY: 70488

Gnomad AFR exome AF: 0.932

Gnomad AMR exome AF: 0.658

Gnomad ASJ exome AF: 0.565

Gnomad EAS exome AF: 0.808

Gnomad SAS exome AF: 0.607

Gnomad FIN exome AF: 0.679

Gnomad NFE exome AF: 0.712

Gnomad OTH exome AF: 0.696

GnomAD4 exome AF: 0.687 AC: 249403 AN: 362884 Hom.: 87086 Cov.: 1 AF XY: 0.679 AC XY: 137380 AN XY: 202400

Gnomad4 AFR exome AF: 0.923

Gnomad4 AMR exome AF: 0.661

Gnomad4 ASJ exome AF: 0.561

Gnomad4 EAS exome AF: 0.799

Gnomad4 SAS exome AF: 0.605

Gnomad4 FIN exome AF: 0.666

Gnomad4 NFE exome AF: 0.704

Gnomad4 OTH exome AF: 0.702

GnomAD4 genome AF: 0.760 AC: 115310 AN: 151662 Hom.: 44699 Cov.: 29 AF XY: 0.757 AC XY: 56063 AN XY: 74058

Gnomad4 AFR AF: 0.923

Gnomad4 AMR AF: 0.706

Gnomad4 ASJ AF: 0.553

Gnomad4 EAS AF: 0.804

Gnomad4 SAS AF: 0.628

Gnomad4 FIN AF: 0.677

Gnomad4 NFE AF: 0.704

Gnomad4 OTH AF: 0.733

Alfa AF: 0.708 Hom.: 4619

Bravo AF: 0.772

Asia WGS AF: 0.750 AC: 2605 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 10, 2019	- -

Usher syndrome type 3 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.90
DANN	Benign	0.57

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: rs1456138; hg19: chr3-150645408;