3-150927631-TACACACACACACACAC-TACACACACACACACACAC

Variant names:

• chr3-150927631-T-TAC
• rs34027634
• NM_174878.3:c.*303_*304dupGT

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6 BA1

The NM_174878.3(CLRN1):​c.*303_*304dupGT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.024 (80 hom., cov: 0)
  • Exomes 𝑓: 0.012 (2 hom.)
• Consequence: CLRN1 NM_174878.3 3_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: -0.454
• 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: Benign. The variant received -9 ACMG points.

• BP6: Variant 3-150927631-T-TAC is Benign according to our data. Variant chr3-150927631-T-TAC is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 343807.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0531 is higher than 0.05.

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.*303_*304dupGT		3_prime_UTR	Exon 3 of 3	NP_777367.1	P58418-3
	CLRN1	NM_001195794.1		c.*303_*304dupGT		3_prime_UTR	Exon 4 of 4	NP_001182723.1	P58418-4
	CLRN1	NM_001256819.2		c.*616_*617dupGT		3_prime_UTR	Exon 4 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.*303_*304dupGT		3_prime_UTR	Exon 3 of 3	ENSP00000322280.1	P58418-3
	CLRN1	ENST00000295911.6	TSL:1	c.342+432_342+433dupGT		intron	N/A	ENSP00000295911.2	P58418-1
	ENSG00000260234	ENST00000562308.5	TSL:1	n.103+13949_103+13950dupGT		intron	N/A	ENSP00000457487.1	H3BU62

Frequencies

GnomAD3 genomes AF: 0.0242 AC: 3600 AN: 148690 Hom.: 80 Cov.: 0

Gnomad AFR AF: 0.0549

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00893

Gnomad ASJ AF: 0.00965

Gnomad EAS AF: 0.00508

Gnomad SAS AF: 0.0167

Gnomad FIN AF: 0.0504

Gnomad MID AF: 0.0258

Gnomad NFE AF: 0.00850

Gnomad OTH AF: 0.0174

GnomAD2 exomes AF: 0.0133 AC: 1325 AN: 99722 AF XY: 0.0133

Gnomad AFR exome AF: 0.0558

Gnomad AMR exome AF: 0.00726

Gnomad ASJ exome AF: 0.00930

Gnomad EAS exome AF: 0.00523

Gnomad FIN exome AF: 0.0499

Gnomad NFE exome AF: 0.00826

Gnomad OTH exome AF: 0.0125

GnomAD4 exome AF: 0.0119 AC: 3854 AN: 323720 Hom.: 2 Cov.: 0 AF XY: 0.0115 AC XY: 2082 AN XY: 180926

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0496 AC: 484 AN: 9760

American (AMR) AF: 0.00674 AC: 179 AN: 26570

Ashkenazi Jewish (ASJ) AF: 0.00821 AC: 101 AN: 12298

East Asian (EAS) AF: 0.00560 AC: 74 AN: 13212

South Asian (SAS) AF: 0.0143 AC: 768 AN: 53612

European-Finnish (FIN) AF: 0.0474 AC: 646 AN: 13642

Middle Eastern (MID) AF: 0.0110 AC: 15 AN: 1362

European-Non Finnish (NFE) AF: 0.00775 AC: 1370 AN: 176790

Other (OTH) AF: 0.0132 AC: 217 AN: 16474

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0243 AC: 3614 AN: 148802 Hom.: 80 Cov.: 0 AF XY: 0.0260 AC XY: 1885 AN XY: 72438

African (AFR) AF: 0.0550 AC: 2217 AN: 40332

American (AMR) AF: 0.00886 AC: 132 AN: 14906

Ashkenazi Jewish (ASJ) AF: 0.00965 AC: 33 AN: 3420

East Asian (EAS) AF: 0.00509 AC: 26 AN: 5108

South Asian (SAS) AF: 0.0168 AC: 78 AN: 4656

European-Finnish (FIN) AF: 0.0504 AC: 509 AN: 10108

Middle Eastern (MID) AF: 0.0278 AC: 8 AN: 288

European-Non Finnish (NFE) AF: 0.00852 AC: 571 AN: 67054

Other (OTH) AF: 0.0196 AC: 40 AN: 2036

Alfa AF: 0.0102 Hom.: 963

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	1	-	Retinitis pigmentosa-deafness syndrome (1)
-	1	-	Retinitis Pigmentosa, Dominant (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.45
Mutation Taster		=100/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs34027634; hg19: chr3-150645418;