3-150927564-G-A

Position:

• chr3-150927564-G-A

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.*372C>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 0.708 in 459,622 control chromosomes in the GnomAD database, including 117,380 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.76 (44763 hom., cov: 31)
  • Exomes 𝑓: 0.68 (72617 hom.)
• Consequence: CLRN1 NM_174878.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.721

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=-0.79).
• BP6: Variant 3-150927564-G-A is Benign according to our data. Variant chr3-150927564-G-A is described in ClinVar as [Benign]. Clinvar id is 343804.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.916 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLRN1	NM_174878.3	c.*372C>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.*372C>T		3_prime_UTR_variant	3/3	1	NM_174878.3	ENSP00000322280	P1
CLRN1	ENST00000295911.6	c.342+501C>T		intron_variant		1		ENSP00000295911
	ENST00000469268.1	n.235+36694G>A		intron_variant, non_coding_transcript_variant		4
CLRN1-AS1	ENST00000476886.5	n.123+74958G>A		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.759 AC: 115376 AN: 151944 Hom.: 44719 Cov.: 31

Gnomad AFR AF: 0.923

Gnomad AMI AF: 0.760

Gnomad AMR AF: 0.705

Gnomad ASJ AF: 0.552

Gnomad EAS AF: 0.803

Gnomad SAS AF: 0.628

Gnomad FIN AF: 0.672

Gnomad MID AF: 0.636

Gnomad NFE AF: 0.703

Gnomad OTH AF: 0.730

GnomAD3 exomes AF: 0.688 AC: 88820 AN: 129192 Hom.: 31197 AF XY: 0.680 AC XY: 47915 AN XY: 70434

Gnomad AFR exome AF: 0.931

Gnomad AMR exome AF: 0.658

Gnomad ASJ exome AF: 0.554

Gnomad EAS exome AF: 0.808

Gnomad SAS exome AF: 0.597

Gnomad FIN exome AF: 0.672

Gnomad NFE exome AF: 0.709

Gnomad OTH exome AF: 0.693

GnomAD4 exome AF: 0.682 AC: 209745 AN: 307560 Hom.: 72617 Cov.: 0 AF XY: 0.673 AC XY: 117589 AN XY: 174642

Gnomad4 AFR exome AF: 0.923

Gnomad4 AMR exome AF: 0.658

Gnomad4 ASJ exome AF: 0.560

Gnomad4 EAS exome AF: 0.803

Gnomad4 SAS exome AF: 0.601

Gnomad4 FIN exome AF: 0.669

Gnomad4 NFE exome AF: 0.703

Gnomad4 OTH exome AF: 0.695

GnomAD4 genome AF: 0.759 AC: 115477 AN: 152062 Hom.: 44763 Cov.: 31 AF XY: 0.756 AC XY: 56180 AN XY: 74330

Gnomad4 AFR AF: 0.923

Gnomad4 AMR AF: 0.704

Gnomad4 ASJ AF: 0.552

Gnomad4 EAS AF: 0.803

Gnomad4 SAS AF: 0.628

Gnomad4 FIN AF: 0.672

Gnomad4 NFE AF: 0.703

Gnomad4 OTH AF: 0.733

Alfa AF: 0.705 Hom.: 51561

Bravo AF: 0.772

Asia WGS AF: 0.750 AC: 2594 AN: 3464

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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. -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.30
DANN	Benign	0.79

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: rs4680058; hg19: chr3-150645351;