rs41304641

chr10-54346487-G-A

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_033056.4(PCDH15):c.475-3C>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00923 in 1,613,090 control chromosomes in the GnomAD database, including 101 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0080 (10 hom., cov: 32)
  • Exomes 𝑓: 0.0093 (91 hom.)
• Consequence: PCDH15 NM_033056.4 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.06887
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 2.21

Genes affected

PCDH15 (HGNC:14674): (protocadherin related 15) This gene is a member of the cadherin superfamily. Family members encode integral membrane proteins that mediate calcium-dependent cell-cell adhesion. It plays an essential role in maintenance of normal retinal and cochlear function. Mutations in this gene result in hearing loss and Usher Syndrome Type IF (USH1F). Extensive alternative splicing resulting in multiple isoforms has been observed in the mouse ortholog. Similar alternatively spliced transcripts are inferred to occur in human, and additional variants are likely to occur. [provided by RefSeq, Dec 2008]

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.3).
• BP6: Variant 10-54346487-G-A is Benign according to our data. Variant chr10-54346487-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 46485.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-54346487-G-A is described in Lovd as [Likely_benign]. Variant chr10-54346487-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00804 (1224/152146) while in subpopulation NFE AF= 0.011 (749/67982). AF 95% confidence interval is 0.0104. There are 10 homozygotes in gnomad4. There are 578 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 10 AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCDH15	NM_001384140.1	c.475-3C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000644397.2
PCDH15	NM_033056.4	c.475-3C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000320301.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCDH15	ENST00000320301.11	c.475-3C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_033056.4
PCDH15	ENST00000644397.2	c.475-3C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			NM_001384140.1

Frequencies

GnomAD3 genomes AF: 0.00805 AC: 1224 AN: 152028 Hom.: 10 Cov.: 32

Gnomad AFR AF: 0.00167

Gnomad AMI AF: 0.0846

Gnomad AMR AF: 0.00851

Gnomad ASJ AF: 0.0329

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00249

Gnomad FIN AF: 0.00492

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0110

Gnomad OTH AF: 0.00860

GnomAD3 exomes AF: 0.00831 AC: 2087 AN: 251012 Hom.: 18 AF XY: 0.00865 AC XY: 1174 AN XY: 135700

Gnomad AFR exome AF: 0.00203

Gnomad AMR exome AF: 0.00761

Gnomad ASJ exome AF: 0.0293

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.00399

Gnomad FIN exome AF: 0.00383

Gnomad NFE exome AF: 0.0105

Gnomad OTH exome AF: 0.0163

GnomAD4 exome AF: 0.00935 AC: 13659 AN: 1460944 Hom.: 91 Cov.: 31 AF XY: 0.00934 AC XY: 6787 AN XY: 726796

Gnomad4 AFR exome AF: 0.00137

Gnomad4 AMR exome AF: 0.00812

Gnomad4 ASJ exome AF: 0.0315

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00395

Gnomad4 FIN exome AF: 0.00375

Gnomad4 NFE exome AF: 0.0102

Gnomad4 OTH exome AF: 0.00830

GnomAD4 genome AF: 0.00804 AC: 1224 AN: 152146 Hom.: 10 Cov.: 32 AF XY: 0.00777 AC XY: 578 AN XY: 74408

Gnomad4 AFR AF: 0.00166

Gnomad4 AMR AF: 0.00850

Gnomad4 ASJ AF: 0.0329

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00291

Gnomad4 FIN AF: 0.00492

Gnomad4 NFE AF: 0.0110

Gnomad4 OTH AF: 0.00851

Alfa AF: 0.0102 Hom.: 5

Bravo AF: 0.00846

EpiCase AF: 0.0123

EpiControl AF: 0.0131

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	PCDH15: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 05, 2018	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 08, 2019	Variant summary: PCDH15 c.475-3C>T alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 2/4 computational tools predict that the variant impacts normal splicing by creating a 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0083 in 251012 control chromosomes in the gnomAD database, including 18 homozygotes. The observed variant frequency is approximately 2.63 fold of the estimated maximal expected allele frequency for a pathogenic variant in PCDH15 causing Usher Syndrome Type 1F phenotype (0.0032), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.475-3C>T in individuals affected with Usher Syndrome Type 1F and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar(after 2014) and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 08, 2011	475-3C>T in intron 5 of PCDH15: This variant has previously been identified as a homozygous variant in combination with another likely pathogenic PCDH15 variant in an individual with a clinical diagnosis of Usher syndrome, and therefore the 475-3C>T variant was classified as a polymorphism (http://www.umd.be/PCDH15/). This variant is also listed in dbSNP; however, frequency data is not available ( rs41304641). This variant has been identified by our laboratory in 5/224 (2%) in dividuals tested, none of whom had congenital profound hearing loss consistent w ith pathogenic variants in PCDH15. The 475-3C>T variant is located in the 5' spl ice region but does not affect the highly conserved +1 and +2 positions. In summ ary, this data suggests that this variant is likely to be benign. -

Usher syndrome type 1F Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

Usher syndrome type 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.30
Cadd	Benign	12
Dann	Benign	0.86

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.069
dbscSNV1_RF	Benign	0.18
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

Publications

LitVar

Other links and lift over

dbSNP: rs41304641; hg19: chr10-56106247; COSMIC: COSV57416707;