chr10-101010536-T-TGCTGCGGCTGCG

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP3

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. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. 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

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 0.894

Publications

10 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: Likely_benign. The variant received -1 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_001195263.2

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PDZD7	NM_001195263.2 link	c.2341_2352dupCGCAGCCGCAGC	p.Ser784_Ser785insArgSerArgSer	conservative_inframe_insertion	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.2341_2352dupCGCAGCCGCAGC	p.Ser784_Ser785insArgSerArgSer	conservative_inframe_insertion	Exon 15 of 17	5	NM_001195263.2	ENSP00000480489.1	Q9H5P4-3
PDZD7	ENST00000474125.7 link	n.2288_2299dupCGCAGCCGCAGC		non_coding_transcript_exon_variant	Exon 11 of 13	2		ENSP00000474447.1	S4R3J9
PDZD7	ENST00000474125.7 link	n.2288_2299dupCGCAGCCGCAGC		3_prime_UTR_variant	Exon 11 of 13	2		ENSP00000474447.1	S4R3J9

Frequencies

GnomAD3 genomes

AF:

0.000271

AC:

AN:

151384

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.000210

AC:

AN:

128718

AF XY:

0.000244

show subpopulations

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 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.:

Cov.:

AF XY:

0.000157

AC XY:

106

AN XY:

675330

show subpopulations

African (AFR)

AF:

0.000446

AC:

AN:

31396

American (AMR)

AF:

0.000283

AC:

AN:

35320

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24594

East Asian (EAS)

AF:

0.000845

AC:

AN:

35512

South Asian (SAS)

AF:

0.000166

AC:

AN:

78340

European-Finnish (FIN)

AF:

0.0000596

AC:

AN:

33538

Middle Eastern (MID)

AF:

0.000358

AC:

AN:

5594

European-Non Finnish (NFE)

AF:

0.000123

AC:

132

AN:

1070816

Other (OTH)

AF:

0.000122

AC:

AN:

57346

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

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:

0.000264

AC:

AN:

151498

Hom.:

Cov.:

AF XY:

0.000230

AC XY:

AN XY:

73966

show subpopulations

African (AFR)

AF:

0.000580

AC:

AN:

41400

American (AMR)

AF:

0.0000656

AC:

AN:

15234

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3460

East Asian (EAS)

AF:

0.000967

AC:

AN:

5168

South Asian (SAS)

AF:

0.000417

AC:

AN:

4800

European-Finnish (FIN)

AF:

0.0000957

AC:

AN:

10446

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000886

AC:

AN:

67698

Other (OTH)

AF:

0.000477

AC:

AN:

2098

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

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:

0.0000546

Hom.:

1561

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Aug 24, 2023

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Sep 12, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.89

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