3-150927631-TACACACACACACACAC-TACACACACACACACACACAC

Variant names:

• chr3-150927631-T-TACAC
• rs34027634
• NM_174878.3:c.*301_*304dupGTGT

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_174878.3(CLRN1):​c.*301_*304dupGTGT 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 0.0039 (8 hom., cov: 0)
  • Exomes 𝑓: 0.00055 (0 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-TACAC is Benign according to our data. Variant chr3-150927631-T-TACAC is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 343808.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00389 (579/148822) while in subpopulation AFR AF = 0.0132 (531/40336). AF 95% confidence interval is 0.0122. There are 8 homozygotes in GnomAd4. There are 239 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 8 Unknown,AD,AR gene

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.*301_*304dupGTGT		3_prime_UTR	Exon 3 of 3	NP_777367.1	P58418-3
	CLRN1	NM_001195794.1		c.*301_*304dupGTGT		3_prime_UTR	Exon 4 of 4	NP_001182723.1	P58418-4
	CLRN1	NM_001256819.2		c.*614_*617dupGTGT		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.*301_*304dupGTGT		3_prime_UTR	Exon 3 of 3	ENSP00000322280.1	P58418-3
	CLRN1	ENST00000295911.6	TSL:1	c.342+430_342+433dupGTGT		intron	N/A	ENSP00000295911.2	P58418-1
	ENSG00000260234	ENST00000562308.5	TSL:1	n.103+13947_103+13950dupGTGT		intron	N/A	ENSP00000457487.1	H3BU62

Frequencies

GnomAD3 genomes AF: 0.00388 AC: 577 AN: 148710 Hom.: 8 Cov.: 0

Gnomad AFR AF: 0.0132

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00181

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000195

Gnomad SAS AF: 0.000429

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000119

Gnomad OTH AF: 0.00497

GnomAD2 exomes AF: 0.000953 AC: 95 AN: 99722 AF XY: 0.000719

Gnomad AFR exome AF: 0.0163

Gnomad AMR exome AF: 0.000263

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000240

Gnomad NFE exome AF: 0.0000265

Gnomad OTH exome AF: 0.000656

GnomAD4 exome AF: 0.000548 AC: 178 AN: 324558 Hom.: 0 Cov.: 0 AF XY: 0.000397 AC XY: 72 AN XY: 181444

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

African (AFR) AF: 0.0129 AC: 126 AN: 9788

American (AMR) AF: 0.000489 AC: 13 AN: 26608

Ashkenazi Jewish (ASJ) AF: 0.0000811 AC: 1 AN: 12336

East Asian (EAS) AF: 0.00 AC: 0 AN: 13222

South Asian (SAS) AF: 0.000334 AC: 18 AN: 53836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 13684

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1362

European-Non Finnish (NFE) AF: 0.0000564 AC: 10 AN: 177200

Other (OTH) AF: 0.000605 AC: 10 AN: 16522

⚠️ 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: 0.00389 AC: 579 AN: 148822 Hom.: 8 Cov.: 0 AF XY: 0.00330 AC XY: 239 AN XY: 72456

African (AFR) AF: 0.0132 AC: 531 AN: 40336

American (AMR) AF: 0.00181 AC: 27 AN: 14908

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3420

East Asian (EAS) AF: 0.000196 AC: 1 AN: 5108

South Asian (SAS) AF: 0.000430 AC: 2 AN: 4656

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10114

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 288

European-Non Finnish (NFE) AF: 0.000119 AC: 8 AN: 67062

Other (OTH) AF: 0.00491 AC: 10 AN: 2036

Alfa AF: 0.000471 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;