rs555444131

Variant names:

• chr10-101018270-TCTC-T
• rs555444131
• NM_001195263.2:c.1348_1350delGAG

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PM4_Supporting BP6 BS1 BS2

The NM_001195263.2(PDZD7):​c.1348_1350delGAG​(p.Glu450del) variant causes a conservative inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000747 in 1,613,768 control chromosomes in the GnomAD database, including 8 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00042 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00078 (8 hom.)
• Consequence: PDZD7 NM_001195263.2 conservative_inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:4
• Conservation: PhyloP100: 3.54

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 -8 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_001195263.2. Strenght limited to Supporting due to length of the change: 1aa.
• BP6: Variant 10-101018270-TCTC-T is Benign according to our data. Variant chr10-101018270-TCTC-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 178694.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=1, Likely_benign=2}. Variant chr10-101018270-TCTC-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000421 (64/152134) while in subpopulation SAS AF= 0.00395 (19/4812). AF 95% confidence interval is 0.00259. There are 0 homozygotes in gnomad4. There are 27 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 8 AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PDZD7	NM_001195263.2	c.1348_1350delGAG	p.Glu450del	conservative_inframe_deletion	Exon 9 of 17	ENST00000619208.6	NP_001182192.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PDZD7	ENST00000619208.6	c.1348_1350delGAG	p.Glu450del	conservative_inframe_deletion	Exon 9 of 17	5	NM_001195263.2	ENSP00000480489.1

Frequencies

GnomAD3 genomes AF: 0.000421 AC: 64 AN: 152016 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00395

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000559

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000907 AC: 228 AN: 251294 Hom.: 3 AF XY: 0.00121 AC XY: 164 AN XY: 135842

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.00526

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000475

Gnomad OTH exome AF: 0.000652

GnomAD4 exome AF: 0.000781 AC: 1141 AN: 1461634 Hom.: 8 AF XY: 0.000941 AC XY: 684 AN XY: 727114

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.0000765

Gnomad4 EAS exome AF: 0.000151

Gnomad4 SAS exome AF: 0.00535

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000550

Gnomad4 OTH exome AF: 0.000629

GnomAD4 genome AF: 0.000421 AC: 64 AN: 152134 Hom.: 0 Cov.: 32 AF XY: 0.000363 AC XY: 27 AN XY: 74378

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00395

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000559

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000364 Hom.: 0

Bravo AF: 0.000389

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.000436

EpiControl AF: 0.000711

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 13, 2025	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 20, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 12, 2014	- -

Retinal dystrophy Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Jan 01, 2022

- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 14, 2013

Glu450del in exon 9 of PDZD7: This variant is not expected to have clinical sign ificance due to a lack of conservation across species, including mammals. Of no te, the marmoset has an in-frame deletion of the glutamate (Glu) at this positio n. -

PDZD7-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 06, 2024

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

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs555444131; hg19: chr10-102778027;