3-150926972-G-A

Position:

• chr3-150926972-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.*964C>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 0.00698 in 1,588,004 control chromosomes in the GnomAD database, including 667 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.036 (365 hom., cov: 32)
  • Exomes 𝑓: 0.0039 (302 hom.)
• Consequence: CLRN1 ENST00000327047.6 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.157

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 3-150926972-G-A is Benign according to our data. Variant chr3-150926972-G-A is described in ClinVar as [Benign]. Clinvar id is 343800.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-150926972-G-A is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.124 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLRN1	NM_174878.3	c.*964C>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.*964C>T		3_prime_UTR_variant	3/3	1	NM_174878.3	ENSP00000322280	P1
CLRN1	ENST00000295911.6	c.343-100C>T		intron_variant		1		ENSP00000295911
	ENST00000469268.1	n.235+36102G>A		intron_variant, non_coding_transcript_variant		4
CLRN1-AS1	ENST00000476886.5	n.123+74366G>A		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.0364 AC: 5535 AN: 152096 Hom.: 367 Cov.: 32

Gnomad AFR AF: 0.127

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0120

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000412

Gnomad OTH AF: 0.0249

GnomAD3 exomes AF: 0.00985 AC: 2235 AN: 226906 Hom.: 110 AF XY: 0.00717 AC XY: 873 AN XY: 121790

Gnomad AFR exome AF: 0.130

Gnomad AMR exome AF: 0.00795

Gnomad ASJ exome AF: 0.00210

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000280

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000489

Gnomad OTH exome AF: 0.00579

GnomAD4 exome AF: 0.00386 AC: 5541 AN: 1435790 Hom.: 302 Cov.: 26 AF XY: 0.00336 AC XY: 2399 AN XY: 714022

Gnomad4 AFR exome AF: 0.129

Gnomad4 AMR exome AF: 0.00860

Gnomad4 ASJ exome AF: 0.00221

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000343

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000282

Gnomad4 OTH exome AF: 0.00829

GnomAD4 genome AF: 0.0364 AC: 5536 AN: 152214 Hom.: 365 Cov.: 32 AF XY: 0.0347 AC XY: 2580 AN XY: 74422

Gnomad4 AFR AF: 0.127

Gnomad4 AMR AF: 0.0120

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000426

Gnomad4 OTH AF: 0.0246

Alfa AF: 0.0125 Hom.: 42

Bravo AF: 0.0418

Asia WGS AF: 0.00635 AC: 22 AN: 3478

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	Dec 18, 2018	- -

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	0.85
DANN	Benign	0.61

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: rs16863066; hg19: chr3-150644759;