rs11004527

Variant names:

• chr10-54740894-A-G
• rs11004527
• NM_033056.4:c.-29+60031T>C

Variant summary

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

The NM_033056.4(PCDH15):​c.-29+60031T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.126 in 151,872 control chromosomes in the GnomAD database, including 1,362 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 0.13 (1362 hom., cov: 32)
• Consequence: PCDH15 NM_033056.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.624
• Publications: 1 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=-1.04).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.176 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCDH15	NM_033056.4	c.-29+60031T>C		intron_variant	Intron 1 of 32	ENST00000320301.11	NP_149045.3
PCDH15	NM_001384140.1	c.-29+60031T>C		intron_variant	Intron 1 of 37	ENST00000644397.2	NP_001371069.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCDH15	ENST00000320301.11	c.-29+60031T>C		intron_variant	Intron 1 of 32	1	NM_033056.4	ENSP00000322604.6
PCDH15	ENST00000644397.2	c.-29+60031T>C		intron_variant	Intron 1 of 37		NM_001384140.1	ENSP00000495195.1

Frequencies

GnomAD3 genomes AF: 0.126 AC: 19046 AN: 151754 Hom.: 1362 Cov.: 32

Gnomad AFR AF: 0.180

Gnomad AMI AF: 0.225

Gnomad AMR AF: 0.136

Gnomad ASJ AF: 0.166

Gnomad EAS AF: 0.0563

Gnomad SAS AF: 0.0859

Gnomad FIN AF: 0.0843

Gnomad MID AF: 0.123

Gnomad NFE AF: 0.101

Gnomad OTH AF: 0.130

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

GnomAD4 genome AF: 0.126 AC: 19062 AN: 151872 Hom.: 1362 Cov.: 32 AF XY: 0.125 AC XY: 9250 AN XY: 74232

African (AFR) AF: 0.180 AC: 7457 AN: 41462

American (AMR) AF: 0.136 AC: 2067 AN: 15214

Ashkenazi Jewish (ASJ) AF: 0.166 AC: 577 AN: 3466

East Asian (EAS) AF: 0.0563 AC: 290 AN: 5154

South Asian (SAS) AF: 0.0860 AC: 414 AN: 4814

European-Finnish (FIN) AF: 0.0843 AC: 893 AN: 10590

Middle Eastern (MID) AF: 0.126 AC: 37 AN: 294

European-Non Finnish (NFE) AF: 0.101 AC: 6848 AN: 67854

Other (OTH) AF: 0.130 AC: 274 AN: 2114

Alfa AF: 0.114 Hom.: 164

Bravo AF: 0.137

Asia WGS AF: 0.0800 AC: 280 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	1.8
DANN	Benign	0.48
PhyloP100		-0.62
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: rs11004527; hg19: chr10-56500654;