chr10-53875264-G-A

Variant names:

• chr10-53875264-G-A
• rs4478893
• NM_033056.4:c.3502-8407C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_033056.4(PCDH15):​c.3502-8407C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.733 in 151,816 control chromosomes in the GnomAD database, including 41,239 homozygotes. 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 0.73 (41239 hom., cov: 31)
• Consequence: PCDH15 NM_033056.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.526
• Publications: 2 publications found

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]

PCDH15 Gene-Disease associations (from GenCC):

• autosomal recessive nonsyndromic hearing loss 23

  Inheritance: AR Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), PanelApp Australia
• Usher syndrome type 1

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Usher syndrome type 1F

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), PanelApp Australia
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.99).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.844 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCDH15	NM_033056.4	c.3502-8407C>T		intron_variant	Intron 26 of 32	ENST00000320301.11	NP_149045.3
PCDH15	NM_001384140.1	c.3502-8407C>T		intron_variant	Intron 26 of 37	ENST00000644397.2	NP_001371069.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCDH15	ENST00000320301.11	c.3502-8407C>T		intron_variant	Intron 26 of 32	1	NM_033056.4	ENSP00000322604.6
PCDH15	ENST00000644397.2	c.3502-8407C>T		intron_variant	Intron 26 of 37		NM_001384140.1	ENSP00000495195.1

Frequencies

GnomAD3 genomes AF: 0.733 AC: 111241 AN: 151700 Hom.: 41222 Cov.: 31

Gnomad AFR AF: 0.805

Gnomad AMI AF: 0.743

Gnomad AMR AF: 0.804

Gnomad ASJ AF: 0.820

Gnomad EAS AF: 0.866

Gnomad SAS AF: 0.728

Gnomad FIN AF: 0.677

Gnomad MID AF: 0.833

Gnomad NFE AF: 0.667

Gnomad OTH AF: 0.757

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.733 AC: 111313 AN: 151816 Hom.: 41239 Cov.: 31 AF XY: 0.739 AC XY: 54812 AN XY: 74208

African (AFR) AF: 0.804 AC: 33346 AN: 41454

American (AMR) AF: 0.804 AC: 12275 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.820 AC: 2844 AN: 3468

East Asian (EAS) AF: 0.866 AC: 4470 AN: 5164

South Asian (SAS) AF: 0.728 AC: 3502 AN: 4810

European-Finnish (FIN) AF: 0.677 AC: 7054 AN: 10426

Middle Eastern (MID) AF: 0.834 AC: 242 AN: 290

European-Non Finnish (NFE) AF: 0.667 AC: 45310 AN: 67922

Other (OTH) AF: 0.755 AC: 1592 AN: 2110

Alfa AF: 0.699 Hom.: 62532

Bravo AF: 0.746

Asia WGS AF: 0.780 AC: 2703 AN: 3464

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	0.33
DANN	Benign	0.20
PhyloP100		-0.53
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4478893; hg19: chr10-55635024;