rs397516636

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PM4_SupportingPP5

The NM_001195263.2(PDZD7):c.2675_2677del(p.Lys892del) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000391 in 1,535,908 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000043 ( 0 hom. )

Consequence

PDZD7
NM_001195263.2 inframe_deletion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:1

Conservation

PhyloP100: 7.47

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM4

Nonframeshift variant in NON repetitive region in NM_001195263.2. Strenght limited to Supporting due to length of the change: 1aa.

PP5

Variant 10-101009290-ATCT-A is Pathogenic according to our data. Variant chr10-101009290-ATCT-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 44131.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
PDZD7	NM_001195263.2 linkuse as main transcript	c.2675_2677del	p.Lys892del	inframe_deletion	16/17	ENST00000619208.6
PDZD7	XM_011540177.4 linkuse as main transcript	c.2675_2677del	p.Lys892del	inframe_deletion	17/18
PDZD7	XM_011540178.4 linkuse as main transcript	c.2672_2674del	p.Lys891del	inframe_deletion	16/17
PDZD7	XM_047425767.1 linkuse as main transcript	c.2675_2677del	p.Lys892del	inframe_deletion	16/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PDZD7	ENST00000619208.6 linkuse as main transcript	c.2675_2677del	p.Lys892del	inframe_deletion	16/17	5	NM_001195263.2	P1	Q9H5P4-3
PDZD7	ENST00000474125.7 linkuse as main transcript	c.2622_2624del		3_prime_UTR_variant, NMD_transcript_variant	12/13	2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000365

AC:

AN:

136880

Hom.:

AF XY:

0.0000538

AC XY:

AN XY:

74410

show subpopulations

Gnomad AFR exome

AF:

0.000155

Gnomad AMR exome

AF:

0.00

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:

0.0000746

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000426

AC:

AN:

1383734

Hom.:

AF XY:

0.0000469

AC XY:

AN XY:

682816

show subpopulations

Gnomad4 AFR exome

AF:

0.0000317

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000528

Gnomad4 OTH exome

AF:

0.0000173

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152174

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74340

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Nov 27, 2023

This variant, c.2675_2677del, results in the deletion of 1 amino acid(s) of the PDZD7 protein (p.Lys892del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs397516636, gnomAD 0.02%). This variant has been observed in individual(s) with congenital sensorineural hearing loss (PMID: 34387732). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 44131). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. For these reasons, this variant has been classified as Pathogenic. -

Hearing loss, autosomal recessive 57

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Service de Biologie Medicale, CIUSSS du Saguenay-Lac-Saint-Jean

Dec 01, 2019

- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jan 14, 2013

Variant classified as Uncertain Significance - Favor Benign. The Lys892del in PD ZD7 has not been reported in the literature nor previously identified by our lab oratory. This variant results in an in-frame single amino acid deletion in exon 16 which is only present in an alternate longer transcript of PDZD7, with the ma jor transcript only encoding 10 exons. Furthermore, there is inconclusive eviden ce as to the role of the PDZD7 gene in hearing loss or Usher syndrome. No bialle lic mutations have been found in Usher patients to date despite screening in 205 cases (Ebermann 2010, Besnard 2012). Instead, there is one case report suggesti ng PDZD7 may be a modifier of the severity of Usher syndrome (Ebermann 2010). In addition, there is a second case report suggesting PDZD7 could cause nonsyndrom ic hearing loss based upon a patient with a homozygous translocation that disrup ts the long alternate isoform of PDZD7 (Schneider 2009). It should be noted that the affected individual did not have evidence of retinal disease at age 8 but a dditional evaluations beyond age 8 have not been reported. In summary, additiona l data is needed to determine the clinical significance of this variant; however , based upon the uncertain role of PDZD7 in hearing loss and Usher syndrome and the presence of an alternate cause of hearing loss in this patient, we would lea n towards a more likely benign role. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over