10-53866774-A-C

Variant names:

• chr10-53866774-A-C
• rs397517457
• NM_033056.4:c.3585T>G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001384140.1(PCDH15):​c.3585T>G​(p.Phe1195Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. F1195F) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PCDH15 NM_001384140.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.76

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.958

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCDH15	NM_033056.4	c.3585T>G	p.Phe1195Leu	missense_variant	Exon 27 of 33	ENST00000320301.11	NP_149045.3
PCDH15	NM_001384140.1	c.3585T>G	p.Phe1195Leu	missense_variant	Exon 27 of 38	ENST00000644397.2	NP_001371069.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCDH15	ENST00000320301.11	c.3585T>G	p.Phe1195Leu	missense_variant	Exon 27 of 33	1	NM_033056.4	ENSP00000322604.6
PCDH15	ENST00000644397.2	c.3585T>G	p.Phe1195Leu	missense_variant	Exon 27 of 38		NM_001384140.1	ENSP00000495195.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.10	T;.;.;.;.;T;T;T;T;.;.;T;.;T;.;.;.;.;.;.;T
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.88	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.31	D
MutationAssessor	Pathogenic	3.4	.;.;.;.;M;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;M
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-4.7	.;.;.;.;.;.;.;D;.;D;D;.;D;.;.;D;D;D;.;D;D
REVEL	Pathogenic	0.86
Sift	Pathogenic	0.0	.;.;.;.;.;.;.;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
Polyphen		1.0, 1.0, 0.99, 1.0	.;.;.;.;.;.;.;.;.;.;D;.;D;.;.;D;D;D;.;D;D
Vest4		0.98
MutPred		0.87		Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);.;Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);.;Loss of sheet (P = 0.0817);.;.;.;Loss of sheet (P = 0.0817);.;.;.;.;Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);.;.;.;Loss of sheet (P = 0.0817);
MVP		0.87
MPC		0.23
ClinPred		0.99	D
GERP RS		0.60
Varity_R		0.31
gMVP		0.81

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

Other links and lift over

dbSNP: rs397517457; hg19: chr10-55626534;