10-101010532-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_StrongBP6BS1BS2_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. 10/14 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

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3

Conservation

PhyloP100: -0.674

Publications

0 publications found

Variant links:

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]

PDZD7 Gene-Disease associations (from GenCC):

hearing loss, autosomal recessive
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
hearing loss, autosomal recessive 57
Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae)
Usher syndrome type 2C
Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

PDZD7 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 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 VariationId is 178524.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000982 (136/138444) while in subpopulation AFR AF = 0.00296 (121/40822). AF 95% confidence interval is 0.00253. There are 0 homozygotes in GnomAd4. There are 67 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 2 AR,Unknown 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 rank	MANE	Protein	UniProt
PDZD7	NM_001195263.2 link	c.2357G>A	p.Arg786Gln	missense_variant	Exon 15 of 17	ENST00000619208.6	NP_001182192.1	Q9H5P4-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PDZD7	ENST00000619208.6 link	c.2357G>A	p.Arg786Gln	missense_variant	Exon 15 of 17	5	NM_001195263.2	ENSP00000480489.1	Q9H5P4-3
PDZD7	ENST00000474125.7 link	n.*2304G>A		non_coding_transcript_exon_variant	Exon 11 of 13	2		ENSP00000474447.1	S4R3J9
PDZD7	ENST00000474125.7 link	n.*2304G>A		3_prime_UTR_variant	Exon 11 of 13	2		ENSP00000474447.1	S4R3J9

Frequencies

GnomAD3 genomes

AF:

0.000925

AC:

128

AN:

138332

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.000198

AC:

AN:

126132

AF XY:

0.000146

show subpopulations

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 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.:

Cov.:

AF XY:

0.000102

AC XY:

AN XY:

678576

show subpopulations

African (AFR)

AF:

0.00318

AC:

100

AN:

31446

American (AMR)

AF:

0.000226

AC:

AN:

35474

Ashkenazi Jewish (ASJ)

AF:

0.000120

AC:

AN:

24986

East Asian (EAS)

AF:

0.00

AC:

AN:

35518

South Asian (SAS)

AF:

0.0000254

AC:

AN:

78894

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33756

Middle Eastern (MID)

AF:

0.000353

AC:

AN:

5670

European-Non Finnish (NFE)

AF:

0.00000558

AC:

AN:

1074340

Other (OTH)

AF:

0.000730

AC:

AN:

57562

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000982

AC:

136

AN:

138444

Hom.:

Cov.:

AF XY:

0.000993

AC XY:

AN XY:

67476

show subpopulations

African (AFR)

AF:

0.00296

AC:

121

AN:

40822

American (AMR)

AF:

0.000665

AC:

AN:

13536

Ashkenazi Jewish (ASJ)

AF:

0.000328

AC:

AN:

3050

East Asian (EAS)

AF:

0.00

AC:

AN:

5152

South Asian (SAS)

AF:

0.000232

AC:

AN:

4302

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8992

Middle Eastern (MID)

AF:

0.00

AC:

AN:

278

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

59704

Other (OTH)

AF:

0.00212

AC:

AN:

1888

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00187

Hom.:

Bravo

AF:

0.00106

ExAC

AF:

0.000153

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Dec 05, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PDZD7: BP4 -

Oct 29, 2020

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Sep 08, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

BayesDel_noAF

Benign

-0.51

CADD

Benign

0.83

(source)

DANN

Benign

0.89

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.041

LIST_S2

Benign

0.31

.;T

MetaRNN

Benign

0.0085

T;T

MetaSVM

Benign

-1.0

PhyloP100

-0.67

PrimateAI

Benign

0.45

Sift4G

Benign

0.67

.;T

Vest4

0.10

MVP

0.043

ClinPred

0.015

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over