10-101008523-AG-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PVS1_Moderate PM2

The NM_001195263.2(PDZD7):c.3045del(p.Ser1016ProfsTer29) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000441 in 1,359,514 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. P1015P) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000044 (0 hom.)
• Consequence: PDZD7 NM_001195263.2 frameshift
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.131

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 4 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0184 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PDZD7	NM_001195263.2	c.3045del	p.Ser1016ProfsTer29	frameshift_variant	17/17	ENST00000619208.6
PDZD7	XM_011540177.4	c.3045del	p.Ser1016ProfsTer29	frameshift_variant	18/18
PDZD7	XM_047425767.1	c.3045del	p.Ser1016ProfsTer29	frameshift_variant	17/17
PDZD7	XM_011540178.4	c.3042del	p.Ser1015ProfsTer29	frameshift_variant	17/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PDZD7	ENST00000619208.6	c.3045del	p.Ser1016ProfsTer29	frameshift_variant	17/17	5	NM_001195263.2	P1
PDZD7	ENST00000474125.7	c.*2992del		3_prime_UTR_variant, NMD_transcript_variant	13/13	2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000441 AC: 6 AN: 1359514 Hom.: 0 Cov.: 32 AF XY: 0.00000149 AC XY: 1 AN XY: 671442

Gnomad4 AFR exome AF: 0.0000323

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000127

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000378

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Feb 12, 2020

This sequence change results in a frameshift in the PDZD7 gene (p.Ser1016Profs*29). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 18 amino acids of the PDZD7 protein and extend the protein by an additional 10 amino acids. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. This variant has not been reported in the literature in individuals with PDZD7-related conditions. 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: rs1852289551; hg19: chr10-102768280;