rs111033258

Variant names:

• chr3-150972565-A-C
• rs111033258
• NM_174878.3:c.144T>G

Your query was ambiguous. Multiple possible variants found:

• chr3-150972565-A-C
• chr3-150972565-A-G

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 16P and 1B. PS3 PM1 PM5 PP5_Very_Strong BP4

The NM_174878.3(CLRN1):​c.144T>G​(p.Asn48Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000138 in 1,614,134 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000441715: In vitro functional studies demonstrated that the variant results in misfolding, mislocalization and degradation of the protein, and an absence of the actin reorganizing function (Tian et al. 2009). Gopal et al. (2015) used transgenic zebrafish to show that the variant causes aberrant hair cell bundle morphology with diminished function." and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N48D) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00015 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00014 (1 hom.)
• Consequence: CLRN1 NM_174878.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:21 O:1
• Conservation: PhyloP100: -0.181
• Publications: 59 publications found

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]

ENSG00000243273 (HGNC:):

SIAH2-AS1 (HGNC:40526): (SIAH2 antisense RNA 1)

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

ACMG classification

Our verdict: Pathogenic. The variant received 15 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000441715: In vitro functional studies demonstrated that the variant results in misfolding, mislocalization and degradation of the protein, and an absence of the actin reorganizing function (Tian et al. 2009). Gopal et al. (2015) used transgenic zebrafish to show that the variant causes aberrant hair cell bundle morphology with diminished function.; SCV000699978: "In vitro and in vivo studies showed that this variant leads to mislocalization of CLRN1, disruption of the hair bundle integrity, and hearing loss phenotype (Geng_2012)."; SCV000576656: Published functional studies demonstrate impaired Clrn1 protein localization to the cochlear hair cell bundle (Geng et al., 2012);; SCV000947009: Experimental studies have shown that this missense change affects CLRN1 function (PMID: 22787034, 26180195).; SCV001554304: Functional studies demonstrated that N48K mutants lacked N-linked glycosylation which led to misfolding, mislocalization, and degradation of the CLRN1 protein (Tian_2009_PMID:19423712).; SCV000885202: The asparagine at codon 48 had been experimentally demonstrated to be the sole site of glycosylation on the CLRN1 protein, which may explain the changes in protein localization and stability associated with p.Asn48Lys variant protein (Isosomppi 2000, Tian 2009, Geng 2012). Stable expression of p.Asn48Lys in a Zebrafish model also recapitulates the mis-location of variant protein (Gopal 2015). Finally, a mouse knock-in model of USH3A has demonstrated that mice homozygous for p.Asn48Lys have disrupted hair bundle organization and experience hearing loss by postnatal day 24 to a degree indistinguishable from homozygous CLRN1 knock out mice (Geng 2012).; SCV002507095: Animal models in mice and zebrafish have shown that this variant causes Usher syndrome type 3A (PMID: 26180195, 22787034).
• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in NM_174878.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-150972567-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 48143.
• PP5: Variant 3-150972565-A-C is Pathogenic according to our data. Variant chr3-150972565-A-C is described in ClinVar as Pathogenic. ClinVar VariationId is 4395.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.022752553). . Strength limited to SUPPORTING due to the PP5.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_174878.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLRN1	NM_174878.3	MANE Select	c.144T>G	p.Asn48Lys	missense	Exon 1 of 3	NP_777367.1	P58418-3
	CLRN1	NM_001195794.1		c.144T>G	p.Asn48Lys	missense	Exon 1 of 4	NP_001182723.1	P58418-4
	CLRN1	NM_001256819.2		c.144T>G	p.Asn48Lys	missense	Exon 1 of 4	NP_001243748.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLRN1	ENST00000327047.6	TSL:1 MANE Select	c.144T>G	p.Asn48Lys	missense	Exon 1 of 3	ENSP00000322280.1	P58418-3
	CLRN1	ENST00000328863.8	TSL:1	c.144T>G	p.Asn48Lys	missense	Exon 1 of 4	ENSP00000329158.4	P58418-4
	CLRN1	ENST00000468836.2	TSL:3	c.120T>G	p.Asn40Lys	missense	Exon 1 of 4	ENSP00000419892.2	C9JYI2

Frequencies

GnomAD3 genomes AF: 0.000151 AC: 23 AN: 152240 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00548

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000270 AC: 68 AN: 251460 AF XY: 0.000191

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00575

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000791

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000136 AC: 199 AN: 1461894 Hom.: 1 Cov.: 31 AF XY: 0.000125 AC XY: 91 AN XY: 727248

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00593 AC: 155 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000216 AC: 24 AN: 1112012

Other (OTH) AF: 0.000331 AC: 20 AN: 60396

GnomAD4 genome AF: 0.000151 AC: 23 AN: 152240 Hom.: 0 Cov.: 33 AF XY: 0.000175 AC XY: 13 AN XY: 74380

African (AFR) AF: 0.0000241 AC: 1 AN: 41464

American (AMR) AF: 0.0000654 AC: 1 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00548 AC: 19 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68048

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.000470 Hom.: 0

Bravo AF: 0.000151

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000206 AC: 25

EpiCase AF: 0.0000545

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
7	-	-	Usher syndrome type 3 (7)
5	-	-	not provided (5)
3	-	-	Usher syndrome type 3A (3)
2	-	-	Retinitis pigmentosa (2)
1	-	-	not specified (1)
1	-	-	Retinal dystrophy (1)
1	-	-	Retinitis pigmentosa 61 (1)
1	-	-	Retinitis pigmentosa 61;C5779850:Usher syndrome type 3A (1)
-	-	-	Retinitis pigmentosa;C5779850:Usher syndrome type 3A (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	15
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.72	D
Eigen	Benign	0.0061
Eigen_PC	Benign	-0.16
FATHMM_MKL	Benign	0.67	D
LIST_S2	Uncertain	0.89	D
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.023	T
MetaSVM	Uncertain	-0.10	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		-0.18
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-3.0	D
REVEL	Uncertain	0.52
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.92
MutPred		0.76		Loss of sheet (P = 3e-04)
MVP		0.74
MPC		0.19
ClinPred		0.18	T
GERP RS		-5.2
PromoterAI		-0.025	Neutral
Varity_R		0.75
gMVP		0.86
Mutation Taster		=47/53	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs111033258; hg19: chr3-150690352;