Genetic Variant NM_174878.3:c.433+1106T>A (chr3-150940476-A-T) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_174878.3(CLRN1):c.433+1106T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000586 in 1,534,782 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

CLRN1
NM_174878.3 intron

Scores

Splicing: ADA: 0.00003612

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.275

Publications

2 publications found

Variant links:

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]

CLRN1 links:

ENSG00000260234 (HGNC:):

ENSG00000260234 links:

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

SIAH2-AS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.88).

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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
CLRN1	NM_174878.3	MANE Select	c.433+1106T>A	intron	N/A	NP_777367.1	P58418-3
CLRN1	NM_001195794.1		c.472+5T>A	splice_region intron	N/A	NP_001182723.1	P58418-4
CLRN1	NM_001256819.2		c.*47+1106T>A	intron	N/A	NP_001243748.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
CLRN1	ENST00000327047.6	TSL:1 MANE Select	c.433+1106T>A	intron	N/A	ENSP00000322280.1	P58418-3
CLRN1	ENST00000328863.8	TSL:1	c.472+5T>A	splice_region intron	N/A	ENSP00000329158.4	P58418-4
CLRN1	ENST00000295911.6	TSL:1	c.205+1106T>A	intron	N/A	ENSP00000295911.2	P58418-1

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152242

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000145

AC:

AN:

1382540

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

682238

show subpopulations

African (AFR)

AF:

0.0000634

AC:

AN:

31556

American (AMR)

AF:

0.00

AC:

AN:

35668

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25142

East Asian (EAS)

AF:

0.00

AC:

AN:

35708

South Asian (SAS)

AF:

0.00

AC:

AN:

79060

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33878

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5692

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1077996

Other (OTH)

AF:

0.00

AC:

AN:

57840

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152242

Hom.:

Cov.:

AF XY:

0.0000672

AC XY:

AN XY:

74374

show subpopulations

African (AFR)

AF:

0.000169

AC:

AN:

41462

American (AMR)

AF:

0.00

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5198

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10632

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68048

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000491

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

3.3

(source)

DANN

Benign

0.55

PhyloP100

0.28

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000036

dbscSNV1_RF

Benign

0.014

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over