rs111033496

chr10-53857186-T-Achr10-53857186-T-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_033056.4(PCDH15):c.3795A>T(p.Glu1265Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00262 in 1,597,542 control chromosomes in the GnomAD database, including 114 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. E1265E) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.014 (62 hom., cov: 31)
  • Exomes 𝑓: 0.0014 (52 hom.)
• Consequence: PCDH15 NM_033056.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.0190

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 Benign. Variant got -16 ACMG points.

• BP6: Variant 10-53857186-T-A is Benign according to our data. Variant chr10-53857186-T-A is described in ClinVar as [Benign]. Clinvar id is 46474.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0142 (2153/152150) while in subpopulation AFR AF= 0.0491 (2039/41504). AF 95% confidence interval is 0.0474. There are 62 homozygotes in gnomad4. There are 1051 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 62 AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCDH15	NM_033056.4	c.3795A>T	p.Glu1265Asp	missense_variant	28/33	ENST00000320301.11
PCDH15	NM_001384140.1	c.3795A>T	p.Glu1265Asp	missense_variant	28/38	ENST00000644397.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCDH15	ENST00000320301.11	c.3795A>T	p.Glu1265Asp	missense_variant	28/33	1	NM_033056.4
PCDH15	ENST00000644397.2	c.3795A>T	p.Glu1265Asp	missense_variant	28/38		NM_001384140.1

Frequencies

GnomAD3 genomes AF: 0.0141 AC: 2138 AN: 152034 Hom.: 62 Cov.: 31

Gnomad AFR AF: 0.0489

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00505

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.0125

GnomAD3 exomes AF: 0.00367 AC: 921 AN: 250960 Hom.: 27 AF XY: 0.00274 AC XY: 372 AN XY: 135690

Gnomad AFR exome AF: 0.0507

Gnomad AMR exome AF: 0.00232

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000528

Gnomad OTH exome AF: 0.00131

GnomAD4 exome AF: 0.00141 AC: 2037 AN: 1445392 Hom.: 52 Cov.: 29 AF XY: 0.00120 AC XY: 864 AN XY: 719950

Gnomad4 AFR exome AF: 0.0500

Gnomad4 AMR exome AF: 0.00251

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000187

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000474

Gnomad4 OTH exome AF: 0.00296

GnomAD4 genome AF: 0.0142 AC: 2153 AN: 152150 Hom.: 62 Cov.: 31 AF XY: 0.0141 AC XY: 1051 AN XY: 74390

Gnomad4 AFR AF: 0.0491

Gnomad4 AMR AF: 0.00505

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.0123

Alfa AF: 0.00260 Hom.: 4

Bravo AF: 0.0161

ESP6500AA AF: 0.0470 AC: 207

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00451 AC: 547

Asia WGS AF: 0.00434 AC: 15 AN: 3474

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Sep 17, 2011	Glu1265Asp in exon 28 of PCDH15: Glutamate at position 2072 is not conserved acr oss species (3 other amino acids at this position across 14 species) and the Asp artate variant is present in chicken and frog, suggesting that variation at this position is tolerated and unlikely to disrupt protein function. In addition, th is variant is predicted to be benign by three computational programs (AlignGVGD, SIFT, PolyPhen2). In summary, this variant is likely benign. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 11, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Usher syndrome type 1F Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

Usher syndrome type 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.58
Cadd	Uncertain	24
Dann	Uncertain	0.98
DEOGEN2	Benign	0.0044	T;.;.;.;.;T;.;.;T;T;T;.;.;T;.;T;.;.;.;.;.;.;T
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.15
FATHMM_MKL	Benign	0.74	D
LIST_S2	Uncertain	0.91	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaRNN	Benign	0.0017	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D;D;D;D;N;N;N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.44	T
REVEL	Benign	0.14
Sift4G	Benign	1.0	T;.;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.0010, 0.011, 0.0040, 0.0070	.;.;.;.;.;.;.;.;.;.;.;.;B;.;B;.;.;B;B;B;.;B;B
Vest4		0.15
MutPred		0.48		Gain of sheet (P = 0.039);Gain of sheet (P = 0.039);.;Gain of sheet (P = 0.039);Gain of sheet (P = 0.039);.;.;.;Gain of sheet (P = 0.039);.;.;.;Gain of sheet (P = 0.039);.;.;.;.;Gain of sheet (P = 0.039);Gain of sheet (P = 0.039);.;.;.;Gain of sheet (P = 0.039);
MVP		0.60
MPC		0.027
ClinPred		0.0082	T
GERP RS		5.2
Varity_R		0.088
gMVP		0.39

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.40		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.40		Position offset: -11

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs111033496; hg19: chr10-55616946;