10-54372372-A-T

Variant names:

• chr10-54372372-A-T
• rs4316429
• NM_033056.4:c.319-3097T>A

Variant summary

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

The NM_033056.4(PCDH15):​c.319-3097T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.163 in 151,718 control chromosomes in the GnomAD database, including 2,479 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 0.16 (2479 hom., cov: 32)
• Consequence: PCDH15 NM_033056.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0380
• 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=-0.8).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.274 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCDH15	NM_033056.4	c.319-3097T>A		intron_variant	Intron 4 of 32	ENST00000320301.11	NP_149045.3
PCDH15	NM_001384140.1	c.319-3097T>A		intron_variant	Intron 4 of 37	ENST00000644397.2	NP_001371069.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCDH15	ENST00000320301.11	c.319-3097T>A		intron_variant	Intron 4 of 32	1	NM_033056.4	ENSP00000322604.6
PCDH15	ENST00000644397.2	c.319-3097T>A		intron_variant	Intron 4 of 37		NM_001384140.1	ENSP00000495195.1

Frequencies

GnomAD3 genomes AF: 0.163 AC: 24722 AN: 151600 Hom.: 2469 Cov.: 32

Gnomad AFR AF: 0.278

Gnomad AMI AF: 0.0209

Gnomad AMR AF: 0.107

Gnomad ASJ AF: 0.169

Gnomad EAS AF: 0.0137

Gnomad SAS AF: 0.169

Gnomad FIN AF: 0.151

Gnomad MID AF: 0.213

Gnomad NFE AF: 0.120

Gnomad OTH AF: 0.153

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

GnomAD4 genome AF: 0.163 AC: 24764 AN: 151718 Hom.: 2479 Cov.: 32 AF XY: 0.163 AC XY: 12102 AN XY: 74178

African (AFR) AF: 0.279 AC: 11538 AN: 41420

American (AMR) AF: 0.107 AC: 1621 AN: 15164

Ashkenazi Jewish (ASJ) AF: 0.169 AC: 586 AN: 3464

East Asian (EAS) AF: 0.0140 AC: 72 AN: 5160

South Asian (SAS) AF: 0.169 AC: 815 AN: 4814

European-Finnish (FIN) AF: 0.151 AC: 1596 AN: 10574

Middle Eastern (MID) AF: 0.212 AC: 62 AN: 292

European-Non Finnish (NFE) AF: 0.120 AC: 8135 AN: 67810

Other (OTH) AF: 0.152 AC: 320 AN: 2110

Alfa AF: 0.0563 Hom.: 61

Bravo AF: 0.165

Asia WGS AF: 0.0960 AC: 336 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	7.8
DANN	Benign	0.65
PhyloP100		-0.038
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: rs4316429; hg19: chr10-56132132;