chr10-101010536-T-TGCTGCGGCTGCG

Position:

• chr10-101010536-T-TGCTGCGGCTGCG

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001195263.2(PDZD7):​c.2341_2352dupCGCAGCCGCAGC​(p.Ser784_Ser785insArgSerArgSer) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000164 in 1,523,954 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00026 (0 hom., cov: 0)
  • Exomes 𝑓: 0.00015 (0 hom.)
• Consequence: PDZD7 NM_001195263.2 conservative_inframe_insertion
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.894

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PDZD7	NM_001195263.2	c.2341_2352dupCGCAGCCGCAGC	p.Ser784_Ser785insArgSerArgSer	conservative_inframe_insertion	15/17	ENST00000619208.6	NP_001182192.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PDZD7	ENST00000619208.6	c.2341_2352dupCGCAGCCGCAGC	p.Ser784_Ser785insArgSerArgSer	conservative_inframe_insertion	15/17	5	NM_001195263.2	ENSP00000480489.1
PDZD7	ENST00000474125.7	n.*2288_*2299dupCGCAGCCGCAGC		non_coding_transcript_exon_variant	11/13	2		ENSP00000474447.1
PDZD7	ENST00000474125.7	n.*2288_*2299dupCGCAGCCGCAGC		3_prime_UTR_variant	11/13	2		ENSP00000474447.1

Frequencies

GnomAD3 genomes AF: 0.000271 AC: 41 AN: 151384 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000581

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000657

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000965

Gnomad SAS AF: 0.000624

Gnomad FIN AF: 0.0000957

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000886

Gnomad OTH AF: 0.000482

GnomAD3 exomes AF: 0.000210 AC: 27 AN: 128718 Hom.: 0 AF XY: 0.000244 AC XY: 17 AN XY: 69728

Gnomad AFR exome AF: 0.000623

Gnomad AMR exome AF: 0.000124

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000857

Gnomad SAS exome AF: 0.000279

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000806

Gnomad OTH exome AF: 0.000250

GnomAD4 exome AF: 0.000153 AC: 210 AN: 1372456 Hom.: 0 Cov.: 98 AF XY: 0.000157 AC XY: 106 AN XY: 675330

Gnomad4 AFR exome AF: 0.000446

Gnomad4 AMR exome AF: 0.000283

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000845

Gnomad4 SAS exome AF: 0.000166

Gnomad4 FIN exome AF: 0.0000596

Gnomad4 NFE exome AF: 0.000123

Gnomad4 OTH exome AF: 0.000122

GnomAD4 genome AF: 0.000264 AC: 40 AN: 151498 Hom.: 0 Cov.: 0 AF XY: 0.000230 AC XY: 17 AN XY: 73966

Gnomad4 AFR AF: 0.000580

Gnomad4 AMR AF: 0.0000656

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000967

Gnomad4 SAS AF: 0.000417

Gnomad4 FIN AF: 0.0000957

Gnomad4 NFE AF: 0.0000886

Gnomad4 OTH AF: 0.000477

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 24, 2023	The p.Arg781_Ser784dup variant in PDZD7 has not been previously reported in individuals with hearing loss but has been identified in 0.096% (5/5180) of East Asian and 0.058% (24/41280) of African chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.3.1.2). This variant has also been reported in ClinVar (Variation ID 850611). This variant leads to a duplication of 4 amino acids at position 781 to 784 and is not predicted to alter the protein reading frame. It is unclear if this duplication will impact the protein. In summary, while the clinical significance of this variant is uncertain, its frequency suggests that it is more likely to be benign. ACMG/AMP Criteria applied: BS1. -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 12, 2022	This variant, c.2341_2352dup, results in the insertion of 4 amino acid(s) of the PDZD7 protein (p.Arg781_Ser784dup), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs200896335, gnomAD 0.08%). This variant has not been reported in the literature in individuals affected with PDZD7-related conditions. ClinVar contains an entry for this variant (Variation ID: 850611). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs200896335; hg19: chr10-102770293;