rs4935502

Variant names:

• chr10-54195684-T-A
• rs4935502
• NM_033056.4:c.1304A>T

Your query was ambiguous. Multiple possible variants found:

• chr10-54195684-T-A
• chr10-54195684-T-G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_033056.4(PCDH15):​c.1304A>T​(p.Asp435Val) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 2/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D435A) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PCDH15 NM_033056.4 missense, splice_region
• Scores: Splicing: ADA: 0.9950
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.99
• 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCDH15	NM_033056.4	c.1304A>T	p.Asp435Val	missense_variant, splice_region_variant	Exon 11 of 33	ENST00000320301.11	NP_149045.3
PCDH15	NM_001384140.1	c.1304A>T	p.Asp435Val	missense_variant, splice_region_variant	Exon 11 of 38	ENST00000644397.2	NP_001371069.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCDH15	ENST00000320301.11	c.1304A>T	p.Asp435Val	missense_variant, splice_region_variant	Exon 11 of 33	1	NM_033056.4	ENSP00000322604.6
PCDH15	ENST00000644397.2	c.1304A>T	p.Asp435Val	missense_variant, splice_region_variant	Exon 11 of 38		NM_001384140.1	ENSP00000495195.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.0
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.064	T;.;.;.;.;T;.;T;.;T;T;.;.;T;.;T;.;.;.;.;.;.;T;.
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D;D;D;D;D;D;T;D;D;T;T;T;D;T;D;D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.22	D
MetaRNN	Uncertain	0.71	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.35	T
MutationAssessor	Benign	1.7	.;.;.;.;L;.;.;.;.;.;.;L;.;.;.;.;.;.;.;.;.;.;L;L
PhyloP100		8.0
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-3.6	D;.;.;D;.;.;D;.;D;D;.;D;D;.;D;.;.;D;D;D;.;D;D;D
REVEL	Uncertain	0.41
Sift	Uncertain	0.0020	D;.;.;D;.;.;D;.;T;D;.;D;D;.;D;.;.;D;D;D;.;T;D;D
Sift4G	Uncertain	0.0020	D;.;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
Polyphen		0.98, 1.0, 0.99, 1.0, 1.0, 0.97	.;.;.;.;.;.;.;.;.;.;.;.;D;.;D;.;.;D;D;D;.;D;D;D
Vest4		0.44
MutPred		0.34		Loss of disorder (P = 0.0179);Loss of disorder (P = 0.0179);.;Loss of disorder (P = 0.0179);Loss of disorder (P = 0.0179);.;Loss of disorder (P = 0.0179);Loss of disorder (P = 0.0179);Loss of disorder (P = 0.0179);.;.;Loss of disorder (P = 0.0179);Loss of disorder (P = 0.0179);.;.;.;Loss of disorder (P = 0.0179);Loss of disorder (P = 0.0179);Loss of disorder (P = 0.0179);.;.;Loss of disorder (P = 0.0179);Loss of disorder (P = 0.0179);Loss of disorder (P = 0.0179);
MVP		0.89
MPC		0.21
ClinPred		0.97	D
GERP RS		5.1
PromoterAI		-0.078	Neutral
Varity_R		0.27
gMVP		0.47
Mutation Taster		=53/47	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.92
SpliceAI score (max)		0.020		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: rs4935502; hg19: chr10-55955444;