NM_033056.4:c.4118C>T

Variant names:

• chr10-53831399-G-A
• rs756490783
• NM_033056.4:c.4118C>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP5

The NM_033056.4(PCDH15):​c.4118C>T​(p.Thr1373Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,886 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T1373T) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: PCDH15 NM_033056.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2
• Conservation: PhyloP100: 10.0
• Publications: 5 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
• PP5: Variant 10-53831399-G-A is Pathogenic according to our data. Variant chr10-53831399-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 556004.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCDH15	NM_033056.4	c.4118C>T	p.Thr1373Ile	missense_variant	Exon 30 of 33	ENST00000320301.11	NP_149045.3
PCDH15	NM_001384140.1	c.4118C>T	p.Thr1373Ile	missense_variant	Exon 30 of 38	ENST00000644397.2	NP_001371069.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCDH15	ENST00000320301.11	c.4118C>T	p.Thr1373Ile	missense_variant	Exon 30 of 33	1	NM_033056.4	ENSP00000322604.6
PCDH15	ENST00000644397.2	c.4118C>T	p.Thr1373Ile	missense_variant	Exon 30 of 38		NM_001384140.1	ENSP00000495195.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000119 AC: 3 AN: 251480 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461886 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727246

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112006

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Usher syndrome type 1F Uncertain:2

Jan 05, 2018

Counsyl

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Jan 24, 2023

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

The p.Thr1373Ile variant in PCDH15 has been reported in 2 individuals, in the compound heterozygous state, with Usher syndrome type 1F (PMID: 23767834) and has been identified in 0.02% (3/18394) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs756490783). Although this variant has been seen in the general population in a heterozygous state, its frequency is not high enough to rule out a pathogenic role. This variant has also been reported in ClinVar (Variation ID#: 556004) and has been interpreted as a variant of uncertain significance by Counsyl. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Thr1373Ile variant is uncertain. ACMG/AMP Criteria applied: none (Richards 2015). -

Autosomal recessive nonsyndromic hearing loss 23 Pathogenic:1

Jan 24, 2024

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Pathogenic	0.22
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.057	T;.;.;.;.;T;.;.;T;T;T;.;.;T;.;T;.;.;.;.;.;.;T
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.21	D
MetaRNN	Uncertain	0.72	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	-0.47	T
MutationAssessor	Benign	1.8	.;.;.;.;L;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;L
PhyloP100		10
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-3.3	.;.;.;.;.;.;.;.;.;D;.;D;D;.;D;.;.;D;D;D;.;D;D
REVEL	Uncertain	0.52
Sift	Uncertain	0.0060	.;.;.;.;.;.;.;.;.;D;.;D;D;.;D;.;.;D;D;D;.;D;D
Sift4G	Pathogenic	0.0	D;.;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
Polyphen		1.0, 1.0	.;.;.;.;.;.;.;.;.;.;.;.;D;.;D;.;.;D;D;D;.;D;D
Vest4		0.94
MutPred		0.38		Loss of disorder (P = 0.0404);Loss of disorder (P = 0.0404);.;Loss of disorder (P = 0.0404);Loss of disorder (P = 0.0404);.;.;.;Loss of disorder (P = 0.0404);.;.;.;Loss of disorder (P = 0.0404);.;.;.;.;Loss of disorder (P = 0.0404);Loss of disorder (P = 0.0404);.;.;.;Loss of disorder (P = 0.0404);
MVP		0.85
MPC		0.23
ClinPred		0.85	D
GERP RS		4.8
Varity_R		0.23
gMVP		0.77
Mutation Taster		=0/100	disease causing

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: rs756490783; hg19: chr10-55591159;