10-101008472-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001195263.2(PDZD7):c.3097C>T(p.Pro1033Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000736 in 1,359,452 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 9/12 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1033L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 7.4e-7 (0 hom.)
• Consequence: PDZD7 NM_001195263.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.01

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10096347).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PDZD7	NM_001195263.2	c.3097C>T	p.Pro1033Ser	missense_variant	17/17	ENST00000619208.6
PDZD7	XM_011540177.4	c.3097C>T	p.Pro1033Ser	missense_variant	18/18
PDZD7	XM_047425767.1	c.3097C>T	p.Pro1033Ser	missense_variant	17/17
PDZD7	XM_011540178.4	c.3094C>T	p.Pro1032Ser	missense_variant	17/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PDZD7	ENST00000619208.6	c.3097C>T	p.Pro1033Ser	missense_variant	17/17	5	NM_001195263.2	P1
PDZD7	ENST00000474125.7	c.*3044C>T		3_prime_UTR_variant, NMD_transcript_variant	13/13	2

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 7.36e-7 AC: 1 AN: 1359452 Hom.: 0 Cov.: 32 AF XY: 0.00000150 AC XY: 1 AN XY: 667266

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000134

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 30

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

Apr 18, 2022

This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1033 of the PDZD7 protein (p.Pro1033Ser). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with PDZD7-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0". The serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.0075	T
BayesDel_noAF	Benign	-0.25
Cadd	Benign	16
Dann	Benign	0.80
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.50
FATHMM_MKL	Benign	0.16	N
MetaRNN	Benign	0.10	T;T
MetaSVM	Benign	-1.0	T
PrimateAI	Benign	0.32	T
Vest4		0.14
MVP		0.082
ClinPred		0.26	T
GERP RS		3.3
Varity_R		0.14
gMVP		0.39

Splicing

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr10-102768229;