10-53866870-GAA-GA

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_033056.4(PCDH15):c.3502-14del variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00123 in 1,480,142 control chromosomes in the GnomAD database, including 12 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0028 (1 hom., cov: 22)
  • Exomes 𝑓: 0.0011 (11 hom.)
• Consequence: PCDH15 NM_033056.4 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.936

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 -16 ACMG points.

• BP6: Variant 10-53866870-GA-G is Benign according to our data. Variant chr10-53866870-GA-G is described in ClinVar as [Benign]. Clinvar id is 179543.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-53866870-GA-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00277 (415/150054) while in subpopulation AFR AF= 0.00802 (329/41008). AF 95% confidence interval is 0.00731. There are 1 homozygotes in gnomad4. There are 203 alleles in male gnomad4 subpopulation. Median coverage is 22. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 4 AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCDH15	NM_001384140.1	c.3502-14del		splice_polypyrimidine_tract_variant, intron_variant		ENST00000644397.2
PCDH15	NM_033056.4	c.3502-14del		splice_polypyrimidine_tract_variant, intron_variant		ENST00000320301.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCDH15	ENST00000320301.11	c.3502-14del		splice_polypyrimidine_tract_variant, intron_variant		1	NM_033056.4
PCDH15	ENST00000644397.2	c.3502-14del		splice_polypyrimidine_tract_variant, intron_variant			NM_001384140.1

Frequencies

GnomAD3 genomes AF: 0.00276 AC: 414 AN: 149950 Hom.: 1 Cov.: 22

Gnomad AFR AF: 0.00802

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000996

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00755

Gnomad FIN AF: 0.000399

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000356

Gnomad OTH AF: 0.00146

GnomAD3 exomes AF: 0.00189 AC: 439 AN: 232130 Hom.: 4 AF XY: 0.00204 AC XY: 257 AN XY: 125860

Gnomad AFR exome AF: 0.00869

Gnomad AMR exome AF: 0.000541

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000629

Gnomad SAS exome AF: 0.00813

Gnomad FIN exome AF: 0.000298

Gnomad NFE exome AF: 0.000462

Gnomad OTH exome AF: 0.000538

GnomAD4 exome AF: 0.00106 AC: 1404 AN: 1330088 Hom.: 11 Cov.: 23 AF XY: 0.00122 AC XY: 815 AN XY: 668006

Gnomad4 AFR exome AF: 0.00826

Gnomad4 AMR exome AF: 0.000711

Gnomad4 ASJ exome AF: 0.0000401

Gnomad4 EAS exome AF: 0.0000292

Gnomad4 SAS exome AF: 0.00783

Gnomad4 FIN exome AF: 0.000115

Gnomad4 NFE exome AF: 0.000410

Gnomad4 OTH exome AF: 0.00115

GnomAD4 genome AF: 0.00277 AC: 415 AN: 150054 Hom.: 1 Cov.: 22 AF XY: 0.00278 AC XY: 203 AN XY: 73118

Gnomad4 AFR AF: 0.00802

Gnomad4 AMR AF: 0.000995

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00799

Gnomad4 FIN AF: 0.000399

Gnomad4 NFE AF: 0.000327

Gnomad4 OTH AF: 0.00144

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 28, 2014	3502-14delT in intron 26 of PCDH15: This variant is not expected to have clinic al significance because it is not predicted to alter splicing and has been ident ified in 0.6% (46/8254) European American chromosomes and in 1.2% (53/4264) Afri can American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.wa shington.edu; dbSNP rs5785023). -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 25, 2020	Variant summary: PCDH15 c.3502-14delT alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0019 in 232130 control chromosomes, predominantly at a frequency of 0.0087 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 2.8 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 a benign polymorphism found primarily in populations of African or African-American origin. To our knowledge, no occurrence of c.3502-14delT in individuals affected with Usher Syndrome Type 1F and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as benign. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
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

LitVar

Other links and lift over

dbSNP: rs5785023; hg19: chr10-55626630;