rs76941691

chr10-101018174-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001195263.2(PDZD7):c.1447G>A(p.Asp483Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000782 in 1,614,236 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D483E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0040 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00045 (2 hom.)
• Consequence: PDZD7 NM_001195263.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 3.24

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005961776).
• BP6: Variant 10-101018174-C-T is Benign according to our data. Variant chr10-101018174-C-T is described in ClinVar as [Benign]. Clinvar id is 46207.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-101018174-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00399 (608/152344) while in subpopulation AFR AF= 0.0138 (573/41574). AF 95% confidence interval is 0.0128. There are 3 homozygotes in gnomad4. There are 273 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 3 AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PDZD7	NM_001195263.2	c.1447G>A	p.Asp483Asn	missense_variant	9/17	ENST00000619208.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PDZD7	ENST00000619208.6	c.1447G>A	p.Asp483Asn	missense_variant	9/17	5	NM_001195263.2	P1

Frequencies

GnomAD3 genomes AF: 0.00399 AC: 607 AN: 152226 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.0138

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00150

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00383

GnomAD3 exomes AF: 0.00120 AC: 301 AN: 251472 Hom.: 0 AF XY: 0.000758 AC XY: 103 AN XY: 135918

Gnomad AFR exome AF: 0.0154

Gnomad AMR exome AF: 0.00116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000615

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000447 AC: 654 AN: 1461892 Hom.: 2 Cov.: 33 AF XY: 0.000353 AC XY: 257 AN XY: 727248

Gnomad4 AFR exome AF: 0.0144

Gnomad4 AMR exome AF: 0.00154

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000333

Gnomad4 OTH exome AF: 0.000878

GnomAD4 genome AF: 0.00399 AC: 608 AN: 152344 Hom.: 3 Cov.: 32 AF XY: 0.00366 AC XY: 273 AN XY: 74502

Gnomad4 AFR AF: 0.0138

Gnomad4 AMR AF: 0.00150

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00379

Alfa AF: 0.00136 Hom.: 0

Bravo AF: 0.00443

ESP6500AA AF: 0.0168 AC: 74

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00143 AC: 174

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 30, 2012	Asp483Asn in Exon 09 of PDZD7: This variant is not expected to have clinical sig nificance because it has been identified in 1.6% (58/3738) of African American c hromosomes from a broad population by the NHLBI Exome Sequencing Project (http:/ /evs.gs.washington.edu/EVS; dbSNP rs76941691). -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 26, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 11, 2020	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.74
Cadd	Benign	20
Dann	Uncertain	1.0
DEOGEN2	Benign	0.024	T;T;.;.;.
Eigen	Uncertain	0.27
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.77	D
MetaRNN	Benign	0.0060	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L;L;.;L;.
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.35	T
Polyphen		0.96	D;D;.;.;.
Vest4		0.26, 0.16
MVP		0.38
MPC		0.30
ClinPred		0.025	T
GERP RS		4.1
Varity_R		0.10
gMVP		0.35

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs76941691; hg19: chr10-102777931;