NM_001195263.2:c.2675_2677delAGA
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PM4_SupportingPP5
The NM_001195263.2(PDZD7):c.2675_2677delAGA(p.Lys892del) variant causes a disruptive 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
Consequence
NM_001195263.2 disruptive_inframe_deletion
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PDZD7 | NM_001195263.2 | c.2675_2677delAGA | p.Lys892del | disruptive_inframe_deletion | Exon 16 of 17 | ENST00000619208.6 | NP_001182192.1 | |
PDZD7 | XM_011540177.4 | c.2675_2677delAGA | p.Lys892del | disruptive_inframe_deletion | Exon 17 of 18 | XP_011538479.1 | ||
PDZD7 | XM_047425767.1 | c.2675_2677delAGA | p.Lys892del | disruptive_inframe_deletion | Exon 16 of 17 | XP_047281723.1 | ||
PDZD7 | XM_011540178.4 | c.2672_2674delAGA | p.Lys891del | disruptive_inframe_deletion | Exon 16 of 17 | XP_011538480.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
PDZD7 | ENST00000619208.6 | c.2675_2677delAGA | p.Lys892del | disruptive_inframe_deletion | Exon 16 of 17 | 5 | NM_001195263.2 | ENSP00000480489.1 | ||
PDZD7 | ENST00000474125.7 | n.*2622_*2624delAGA | non_coding_transcript_exon_variant | Exon 12 of 13 | 2 | ENSP00000474447.1 | ||||
PDZD7 | ENST00000474125.7 | n.*2622_*2624delAGA | 3_prime_UTR_variant | Exon 12 of 13 | 2 | ENSP00000474447.1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152174Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000365 AC: 5AN: 136880Hom.: 0 AF XY: 0.0000538 AC XY: 4AN XY: 74410
GnomAD4 exome AF: 0.0000426 AC: 59AN: 1383734Hom.: 0 AF XY: 0.0000469 AC XY: 32AN XY: 682816
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152174Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1AN XY: 74340
ClinVar
Submissions by phenotype
not provided Pathogenic:1
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
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not specified Uncertain:1
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. -
PDZD7-related disorder Uncertain:1
The PDZD7 c.2675_2677delAGA variant is predicted to result in an in-frame deletion (p.Lys892del). This variant was reported in the homozygous or compound heterozygous states along with a premature termination variant in three individuals with hearing loss from two families (Cruz Marino et al. 2022. PubMed ID: 34387732). This variant is reported in 0.016% of alleles in individuals of African descent in gnomAD. Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at