NM_033056.4:c.4368-1125T>C

Variant names:

• chr10-53824483-A-G
• rs1935915
• NM_033056.4:c.4368-1125T>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.4368-1125T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.382 in 151,992 control chromosomes in the GnomAD database, including 12,003 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 0.38 (12003 hom., cov: 32)
• Consequence: PCDH15 NM_033056.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.169
• Publications: 0 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=-0.8).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.718 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCDH15	NM_033056.4	c.4368-1125T>C		intron_variant	Intron 32 of 32	ENST00000320301.11	NP_149045.3
PCDH15	NM_001384140.1	c.4367+2910T>C		intron_variant	Intron 32 of 37	ENST00000644397.2	NP_001371069.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCDH15	ENST00000320301.11	c.4368-1125T>C		intron_variant	Intron 32 of 32	1	NM_033056.4	ENSP00000322604.6
PCDH15	ENST00000644397.2	c.4367+2910T>C		intron_variant	Intron 32 of 37		NM_001384140.1	ENSP00000495195.1

Frequencies

GnomAD3 genomes AF: 0.382 AC: 58075 AN: 151874 Hom.: 12004 Cov.: 32

Gnomad AFR AF: 0.257

Gnomad AMI AF: 0.343

Gnomad AMR AF: 0.415

Gnomad ASJ AF: 0.349

Gnomad EAS AF: 0.737

Gnomad SAS AF: 0.496

Gnomad FIN AF: 0.384

Gnomad MID AF: 0.328

Gnomad NFE AF: 0.419

Gnomad OTH AF: 0.377

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

GnomAD4 genome AF: 0.382 AC: 58093 AN: 151992 Hom.: 12003 Cov.: 32 AF XY: 0.384 AC XY: 28543 AN XY: 74278

African (AFR) AF: 0.256 AC: 10634 AN: 41494

American (AMR) AF: 0.415 AC: 6333 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.349 AC: 1210 AN: 3470

East Asian (EAS) AF: 0.738 AC: 3800 AN: 5150

South Asian (SAS) AF: 0.496 AC: 2394 AN: 4824

European-Finnish (FIN) AF: 0.384 AC: 4061 AN: 10566

Middle Eastern (MID) AF: 0.327 AC: 96 AN: 294

European-Non Finnish (NFE) AF: 0.419 AC: 28457 AN: 67924

Other (OTH) AF: 0.378 AC: 797 AN: 2108

Alfa AF: 0.405 Hom.: 27464

Bravo AF: 0.378

Asia WGS AF: 0.564 AC: 1958 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	1.5
DANN	Benign	0.71
PhyloP100		0.17
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: rs1935915; hg19: chr10-55584243;