rs143414291

Positions:

• chr10-101010745-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_001195263.2(PDZD7):​c.2144C>T​(p.Pro715Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 9/12 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0080 (10 hom., cov: 29)
  • Exomes 𝑓: 0.011 (80 hom.)
  • Failed GnomAD Quality Control
• Consequence: PDZD7 NM_001195263.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 3.25

Genes affected

PDZD7 (HGNC:26257): (PDZ domain containing 7) This gene encodes a ciliary protein homologous to proteins which are mutated in Usher syndrome patients, and mutations and translocations involving this gene have been associated with two types of Usher syndrome. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2010]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0062847733).
• BP6: Variant 10-101010745-G-A is Benign according to our data. Variant chr10-101010745-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 44123.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-101010745-G-A is described in Lovd as [Likely_benign]. Variant chr10-101010745-G-A is described in Lovd as [Benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PDZD7	NM_001195263.2	c.2144C>T	p.Pro715Leu	missense_variant	15/17	ENST00000619208.6	NP_001182192.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PDZD7	ENST00000619208.6	c.2144C>T	p.Pro715Leu	missense_variant	15/17	5	NM_001195263.2	ENSP00000480489.1
PDZD7	ENST00000474125.7	n.*2091C>T		non_coding_transcript_exon_variant	11/13	2		ENSP00000474447.1
PDZD7	ENST00000474125.7	n.*2091C>T		3_prime_UTR_variant	11/13	2		ENSP00000474447.1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 1168 AN: 145922 Hom.: 10 Cov.: 29 FAILED QC

Gnomad AFR AF: 0.00191

Gnomad AMI AF: 0.00454

Gnomad AMR AF: 0.0123

Gnomad ASJ AF: 0.0159

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00321

Gnomad FIN AF: 0.0118

Gnomad MID AF: 0.00974

Gnomad NFE AF: 0.0106

Gnomad OTH AF: 0.0123

GnomAD3 exomes AF: 0.00750 AC: 974 AN: 129826 Hom.: 5 AF XY: 0.00717 AC XY: 510 AN XY: 71156

Gnomad AFR exome AF: 0.00131

Gnomad AMR exome AF: 0.00600

Gnomad ASJ exome AF: 0.0147

Gnomad EAS exome AF: 0.0000959

Gnomad SAS exome AF: 0.00308

Gnomad FIN exome AF: 0.0122

Gnomad NFE exome AF: 0.0109

Gnomad OTH exome AF: 0.00769

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0110 AC: 12944 AN: 1181656 Hom.: 80 Cov.: 43 AF XY: 0.0108 AC XY: 6291 AN XY: 584122

Gnomad4 AFR exome AF: 0.00168

Gnomad4 AMR exome AF: 0.00775

Gnomad4 ASJ exome AF: 0.0189

Gnomad4 EAS exome AF: 0.0000488

Gnomad4 SAS exome AF: 0.00303

Gnomad4 FIN exome AF: 0.0222

Gnomad4 NFE exome AF: 0.0118

Gnomad4 OTH exome AF: 0.0119

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00800 AC: 1168 AN: 146054 Hom.: 10 Cov.: 29 AF XY: 0.00803 AC XY: 571 AN XY: 71112

Gnomad4 AFR AF: 0.00190

Gnomad4 AMR AF: 0.0123

Gnomad4 ASJ AF: 0.0159

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00298

Gnomad4 FIN AF: 0.0118

Gnomad4 NFE AF: 0.0106

Gnomad4 OTH AF: 0.0122

Alfa AF: 0.0101 Hom.: 5

Bravo AF: 0.00798

ExAC AF: 0.00492 AC: 108

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:6

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	PDZD7: BP4, BS1, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 31, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 20, 2019	This variant is associated with the following publications: (PMID: 24498627) -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 23, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 25, 2018	p.Pro715Leu in exon 15 of PDZD7: This variant is not expected to have clinical s ignificance because it has been identified in 4.3% (10/230) of Hispanic chromoso mes from the 1000 Genomes project (http://www.ncbi.nlm.nih.gov/variation/tools/1 000genomes; rs143414291). -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	19
DANN	Benign	0.79
Eigen	Benign	-0.042
Eigen_PC	Benign	0.031
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.63	.;T
MetaRNN	Benign	0.0063	T;T
MetaSVM	Benign	-0.99	T
PrimateAI	Benign	0.47	T
Sift4G	Uncertain	0.021	.;D
Vest4		0.17
MVP		0.093
ClinPred		0.094	T
GERP RS		3.5
Varity_R		0.066
gMVP		0.37

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs143414291; hg19: chr10-102770502; COSMIC: COSV64652378; COSMIC: COSV64652378;