rs555444131

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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:5
• Conservation: PhyloP100: 3.54
• Publications: 4 publications found

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]

PDZD7 Gene-Disease associations (from GenCC):

• hearing loss, autosomal recessive

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• hearing loss, autosomal recessive 57

  Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae)
• Usher syndrome type 2C

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 178694.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 8 AR,Unknown gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001195263.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDZD7	NM_001195263.2	MANE Select	c.1348_1350delGAG	p.Glu450del	conservative_inframe_deletion	Exon 9 of 17	NP_001182192.1
	PDZD7	NM_001437429.1		c.1348_1350delGAG	p.Glu450del	conservative_inframe_deletion	Exon 9 of 17	NP_001424358.1
	PDZD7	NM_024895.5		c.1348_1350delGAG	p.Glu450del	conservative_inframe_deletion	Exon 9 of 10	NP_079171.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDZD7	ENST00000619208.6	TSL:5 MANE Select	c.1348_1350delGAG	p.Glu450del	conservative_inframe_deletion	Exon 9 of 17	ENSP00000480489.1
	PDZD7	ENST00000645349.1		c.1348_1350delGAG	p.Glu450del	conservative_inframe_deletion	Exon 9 of 10	ENSP00000495283.1
	PDZD7	ENST00000644782.1		c.1348_1350delGAG	p.Glu450del	conservative_inframe_deletion	Exon 9 of 12	ENSP00000496747.1

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

GnomAD2 exomes AF: 0.000907 AC: 228 AN: 251294 AF XY: 0.00121

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 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

African (AFR) AF: 0.0000896 AC: 3 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0000765 AC: 2 AN: 26136

East Asian (EAS) AF: 0.000151 AC: 6 AN: 39700

South Asian (SAS) AF: 0.00535 AC: 461 AN: 86240

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00324 AC: 18 AN: 5562

European-Non Finnish (NFE) AF: 0.000550 AC: 612 AN: 1112010

Other (OTH) AF: 0.000629 AC: 38 AN: 60370

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

African (AFR) AF: 0.000120 AC: 5 AN: 41496

American (AMR) AF: 0.0000654 AC: 1 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00395 AC: 19 AN: 4812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10590

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000559 AC: 38 AN: 67986

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

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:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:3

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PDZD7: PM4:Supporting, BS1

Jun 12, 2014

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jul 20, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 13, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Retinal dystrophy Uncertain:1

Jan 01, 2022

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

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

not specified Benign:1

Mar 14, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

May 06, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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 v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.5
Mutation Taster		=64/36	polymorphism

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

Other links and lift over

dbSNP: rs555444131; hg19: chr10-102778027; COSMIC: COSV64646640; COSMIC: COSV64646640;