rs1085307049

Variant names:

• chr3-150928173-CAAT-C
• rs1085307049
• NM_174878.3:c.459_461delATT

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM2 PM4_Supporting PP5_Moderate

The NM_174878.3(CLRN1):​c.459_461delATT​(p.Ile153_Leu154delinsMet) variant causes a disruptive inframe deletion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CLRN1 NM_174878.3 disruptive_inframe_deletion
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 8.17
• Publications: 1 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]

ENSG00000260234 (HGNC:):

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

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_174878.3
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_174878.3. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 3-150928173-CAAT-C is Pathogenic according to our data. Variant chr3-150928173-CAAT-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 4394.Status of the report is criteria_provided_single_submitter, 1 stars.

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.459_461delATT	p.Ile153_Leu154delinsMet	disruptive_inframe_deletion	Exon 3 of 3	NP_777367.1	P58418-3
	CLRN1	NM_001195794.1		c.498_500delATT	p.Ile166_Leu167delinsMet	disruptive_inframe_deletion	Exon 4 of 4	NP_001182723.1	P58418-4
	CLRN1	NM_052995.2		c.231_233delATT	p.Ile77_Leu78delinsMet	disruptive_inframe_deletion	Exon 3 of 4	NP_443721.1	P58418-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLRN1	ENST00000327047.6	TSL:1 MANE Select	c.459_461delATT	p.Ile153_Leu154delinsMet	disruptive_inframe_deletion	Exon 3 of 3	ENSP00000322280.1	P58418-3
	CLRN1	ENST00000328863.8	TSL:1	c.498_500delATT	p.Ile166_Leu167delinsMet	disruptive_inframe_deletion	Exon 4 of 4	ENSP00000329158.4	P58418-4
	CLRN1	ENST00000295911.6	TSL:1	c.231_233delATT	p.Ile77_Leu78delinsMet	disruptive_inframe_deletion	Exon 3 of 4	ENSP00000295911.2	P58418-1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Retinitis pigmentosa 61 (1)
1	-	-	Usher syndrome type 3 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.2
Mutation Taster		=3/197	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.20		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.20		Position offset: 28

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

Other links and lift over

dbSNP: rs1085307049; hg19: chr3-150645960;