rs113570783

Positions:

• chr10-101010532-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Strong BP6 BS2_Supporting

The NM_001195263.2(PDZD7):​c.2357G>A​(p.Arg786Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000197 in 1,516,090 control chromosomes in the GnomAD database, including 2 homozygotes. 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R786W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00098 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00012 (2 hom.)
• Consequence: PDZD7 NM_001195263.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: -0.674

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008478075).
• BP6: Variant 10-101010532-C-T is Benign according to our data. Variant chr10-101010532-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 178524.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}. Variant chr10-101010532-C-T is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAdExome4 at 2 AR,Digenic geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PDZD7	NM_001195263.2	c.2357G>A	p.Arg786Gln	missense_variant	15/17	ENST00000619208.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PDZD7	ENST00000619208.6	c.2357G>A	p.Arg786Gln	missense_variant	15/17	5	NM_001195263.2	P1
PDZD7	ENST00000474125.7	c.*2304G>A		3_prime_UTR_variant, NMD_transcript_variant	11/13	2

Frequencies

GnomAD3 genomes AF: 0.000925 AC: 128 AN: 138332 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00278

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000666

Gnomad ASJ AF: 0.000328

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000232

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00214

GnomAD3 exomes AF: 0.000198 AC: 25 AN: 126132 Hom.: 0 AF XY: 0.000146 AC XY: 10 AN XY: 68504

Gnomad AFR exome AF: 0.00266

Gnomad AMR exome AF: 0.0000849

Gnomad ASJ exome AF: 0.000265

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000468

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000208

Gnomad OTH exome AF: 0.000516

GnomAD4 exome AF: 0.000118 AC: 163 AN: 1377646 Hom.: 2 Cov.: 91 AF XY: 0.000102 AC XY: 69 AN XY: 678576

Gnomad4 AFR exome AF: 0.00318

Gnomad4 AMR exome AF: 0.000226

Gnomad4 ASJ exome AF: 0.000120

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000254

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000558

Gnomad4 OTH exome AF: 0.000730

GnomAD4 genome AF: 0.000982 AC: 136 AN: 138444 Hom.: 0 Cov.: 32 AF XY: 0.000993 AC XY: 67 AN XY: 67476

Gnomad4 AFR AF: 0.00296

Gnomad4 AMR AF: 0.000665

Gnomad4 ASJ AF: 0.000328

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000232

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00212

Alfa AF: 0.000884 Hom.: 0

Bravo AF: 0.00106

ExAC AF: 0.000153 AC: 3

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Dec 19, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Oct 29, 2020	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Sep 08, 2013

Arg786Gln in Exon 15 of PDZD7: This variant is not expected to have clinical sig nficance because the Arg residue at position 786 is not conserved across species and computational tools (biochemical amino acid properties, AlignGVGD, PolyPhen -2, SIFT) suggest that the variant will not impact the protein. This variant is reported in dbSNP in 1/10 individuals from Bushman population (dbSNP rs113570783 ). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	0.83
DANN	Benign	0.89
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.041	N
LIST_S2	Benign	0.31	.;T
MetaRNN	Benign	0.0085	T;T
MetaSVM	Benign	-1.0	T
PrimateAI	Benign	0.45	T
Sift4G	Benign	0.67	.;T
Vest4		0.10
MVP		0.043
ClinPred		0.015	T
GERP RS		-2.9
Varity_R		0.028
gMVP		0.20

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs113570783; hg19: chr10-102770289;