10-53836742-A-G

Variant names:

• chr10-53836742-A-G
• rs1900455
• NM_033056.4:c.3983+3578T>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.3983+3578T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.399 in 152,004 control chromosomes in the GnomAD database, including 12,820 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 0.40 (12820 hom., cov: 32)
• Consequence: PCDH15 NM_033056.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.301
• 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=-0.86).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.734 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCDH15	NM_033056.4	c.3983+3578T>C		intron_variant	Intron 29 of 32	ENST00000320301.11	NP_149045.3
PCDH15	NM_001384140.1	c.3983+3578T>C		intron_variant	Intron 29 of 37	ENST00000644397.2	NP_001371069.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCDH15	ENST00000320301.11	c.3983+3578T>C		intron_variant	Intron 29 of 32	1	NM_033056.4	ENSP00000322604.6
PCDH15	ENST00000644397.2	c.3983+3578T>C		intron_variant	Intron 29 of 37		NM_001384140.1	ENSP00000495195.1

Frequencies

GnomAD3 genomes AF: 0.400 AC: 60694 AN: 151888 Hom.: 12822 Cov.: 32

Gnomad AFR AF: 0.310

Gnomad AMI AF: 0.340

Gnomad AMR AF: 0.415

Gnomad ASJ AF: 0.350

Gnomad EAS AF: 0.753

Gnomad SAS AF: 0.500

Gnomad FIN AF: 0.386

Gnomad MID AF: 0.327

Gnomad NFE AF: 0.423

Gnomad OTH AF: 0.387

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

GnomAD4 genome AF: 0.399 AC: 60707 AN: 152004 Hom.: 12820 Cov.: 32 AF XY: 0.400 AC XY: 29696 AN XY: 74308

African (AFR) AF: 0.309 AC: 12809 AN: 41456

American (AMR) AF: 0.415 AC: 6337 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.350 AC: 1214 AN: 3470

East Asian (EAS) AF: 0.754 AC: 3892 AN: 5162

South Asian (SAS) AF: 0.500 AC: 2412 AN: 4824

European-Finnish (FIN) AF: 0.386 AC: 4076 AN: 10546

Middle Eastern (MID) AF: 0.321 AC: 93 AN: 290

European-Non Finnish (NFE) AF: 0.423 AC: 28744 AN: 67968

Other (OTH) AF: 0.389 AC: 821 AN: 2108

Alfa AF: 0.391 Hom.: 2192

Bravo AF: 0.397

Asia WGS AF: 0.572 AC: 1989 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	1.3
DANN	Benign	0.68
PhyloP100		-0.30
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs1900455; hg19: chr10-55596502;