3-150927052-T-G

Position:

• chr3-150927052-T-G

Variant summary

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

The NM_174878.3(CLRN1):​c.*884A>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0626 in 1,081,344 control chromosomes in the GnomAD database, including 3,940 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.090 (994 hom., cov: 32)
  • Exomes 𝑓: 0.058 (2946 hom.)
• Consequence: CLRN1 NM_174878.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -3.89

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=-0.89).
• BP6: Variant 3-150927052-T-G is Benign according to our data. Variant chr3-150927052-T-G is described in ClinVar as [Benign]. Clinvar id is 343801.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.315 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLRN1	NM_174878.3	c.*884A>C		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.*884A>C		3_prime_UTR_variant	3/3	1	NM_174878.3	ENSP00000322280	P1
CLRN1	ENST00000295911.6	c.343-180A>C		intron_variant		1		ENSP00000295911
	ENST00000469268.1	n.235+36182T>G		intron_variant, non_coding_transcript_variant		4
CLRN1-AS1	ENST00000476886.5	n.123+74446T>G		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.0903 AC: 13737 AN: 152074 Hom.: 992 Cov.: 32

Gnomad AFR AF: 0.151

Gnomad AMI AF: 0.0451

Gnomad AMR AF: 0.116

Gnomad ASJ AF: 0.0435

Gnomad EAS AF: 0.328

Gnomad SAS AF: 0.0570

Gnomad FIN AF: 0.0712

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.0380

Gnomad OTH AF: 0.0771

GnomAD3 exomes AF: 0.0880 AC: 12290 AN: 139644 Hom.: 1031 AF XY: 0.0809 AC XY: 6057 AN XY: 74890

Gnomad AFR exome AF: 0.153

Gnomad AMR exome AF: 0.134

Gnomad ASJ exome AF: 0.0441

Gnomad EAS exome AF: 0.335

Gnomad SAS exome AF: 0.0434

Gnomad FIN exome AF: 0.0701

Gnomad NFE exome AF: 0.0373

Gnomad OTH exome AF: 0.0754

GnomAD4 exome AF: 0.0581 AC: 53954 AN: 929152 Hom.: 2946 Cov.: 13 AF XY: 0.0569 AC XY: 27110 AN XY: 476298

Gnomad4 AFR exome AF: 0.158

Gnomad4 AMR exome AF: 0.132

Gnomad4 ASJ exome AF: 0.0468

Gnomad4 EAS exome AF: 0.283

Gnomad4 SAS exome AF: 0.0450

Gnomad4 FIN exome AF: 0.0668

Gnomad4 NFE exome AF: 0.0394

Gnomad4 OTH exome AF: 0.0767

GnomAD4 genome AF: 0.0904 AC: 13762 AN: 152192 Hom.: 994 Cov.: 32 AF XY: 0.0941 AC XY: 7005 AN XY: 74416

Gnomad4 AFR AF: 0.152

Gnomad4 AMR AF: 0.116

Gnomad4 ASJ AF: 0.0435

Gnomad4 EAS AF: 0.328

Gnomad4 SAS AF: 0.0572

Gnomad4 FIN AF: 0.0712

Gnomad4 NFE AF: 0.0380

Gnomad4 OTH AF: 0.0787

Alfa AF: 0.0529 Hom.: 327

Bravo AF: 0.0986

Asia WGS AF: 0.167 AC: 580 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	Jun 14, 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	-0.89
CADD	Benign	0.010
DANN	Benign	0.73

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: rs12635299; hg19: chr3-150644839; COSMIC: COSV55805628; COSMIC: COSV55805628;