rs200592310

chr10-101019175-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_001195263.2(PDZD7):c.971G>A(p.Ser324Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0025 in 1,537,280 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0017 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0026 (10 hom.)
• Consequence: PDZD7 NM_001195263.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:4
• Conservation: PhyloP100: 4.45

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 Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008763999).
• BP6: Variant 10-101019175-C-T is Benign according to our data. Variant chr10-101019175-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 164942.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=4}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PDZD7	NM_001195263.2	c.971G>A	p.Ser324Asn	missense_variant	8/17	ENST00000619208.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PDZD7	ENST00000619208.6	c.971G>A	p.Ser324Asn	missense_variant	8/17	5	NM_001195263.2	P1

Frequencies

GnomAD3 genomes AF: 0.00171 AC: 261 AN: 152276 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00124

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.000847

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00295

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00181 AC: 250 AN: 137828 Hom.: 0 AF XY: 0.00202 AC XY: 151 AN XY: 74582

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00126

Gnomad ASJ exome AF: 0.000121

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00262

Gnomad FIN exome AF: 0.000727

Gnomad NFE exome AF: 0.00277

Gnomad OTH exome AF: 0.000715

GnomAD4 exome AF: 0.00259 AC: 3588 AN: 1384886 Hom.: 10 Cov.: 33 AF XY: 0.00259 AC XY: 1769 AN XY: 683508

Gnomad4 AFR exome AF: 0.000252

Gnomad4 AMR exome AF: 0.00143

Gnomad4 ASJ exome AF: 0.000159

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00278

Gnomad4 FIN exome AF: 0.00141

Gnomad4 NFE exome AF: 0.00288

Gnomad4 OTH exome AF: 0.00252

GnomAD4 genome AF: 0.00171 AC: 261 AN: 152394 Hom.: 1 Cov.: 32 AF XY: 0.00149 AC XY: 111 AN XY: 74524

Gnomad4 AFR AF: 0.000361

Gnomad4 AMR AF: 0.00124

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00207

Gnomad4 FIN AF: 0.000847

Gnomad4 NFE AF: 0.00295

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00245 Hom.: 1

Bravo AF: 0.00173

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.000255 AC: 1

ESP6500EA AF: 0.00177 AC: 14

ExAC AF: 0.00115 AC: 111

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3 Benign:3

Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 30, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 04, 2021	Identified previously in a patient with retinitis pigmentosa; however, the patient harbored multiple variants in other genes and the S324N variant was not noted to segregate with disease in the family (Borrs et al., 2013); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 23534816) -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Aug 16, 2013

Variant classified as Uncertain Significance - Favor Benign. -

PDZD7-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 15, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.50
Cadd	Pathogenic	27
Dann	Uncertain	1.0
DEOGEN2	Benign	0.034	T;T;.;.;.
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.85	D
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.0088	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.4	M;M;.;M;.
MutationTaster	Benign	0.81	D
PrimateAI	Uncertain	0.50	T
Polyphen		1.0	D;D;.;.;.
Vest4		0.25, 0.19
MVP		0.33
MPC		0.77
ClinPred		0.068	T
GERP RS		4.3
Varity_R		0.25
gMVP		0.49

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: rs200592310; hg19: chr10-102778932;