rs756490783

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP5

The NM_001384140.1(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).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

PCDH15
NM_001384140.1 missense

Scores

7
8
4

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:2

Conservation

PhyloP100: 10.0
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 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: {Likely_pathogenic=1, Uncertain_significance=2}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PCDH15NM_033056.4 linkc.4118C>T p.Thr1373Ile missense_variant Exon 30 of 33 ENST00000320301.11 NP_149045.3 Q96QU1-1
PCDH15NM_001384140.1 linkc.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
PCDH15ENST00000320301.11 linkc.4118C>T p.Thr1373Ile missense_variant Exon 30 of 33 1 NM_033056.4 ENSP00000322604.6 Q96QU1-1
PCDH15ENST00000644397.2 linkc.4118C>T p.Thr1373Ile missense_variant Exon 30 of 38 NM_001384140.1 ENSP00000495195.1 A0A2R8Y6C0

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.0000119
AC:
3
AN:
251480
Hom.:
0
AF XY:
0.00000736
AC XY:
1
AN XY:
135916
show subpopulations
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 SAS exome
AF:
0.00
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
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000504
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.00000756
ExAC
AF:
0.0000165
AC:
2

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:2
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Usher syndrome type 1F Uncertain:2
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). -

Jan 05, 2018
Counsyl
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

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
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

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs756490783; hg19: chr10-55591159; API