rs34616847

Positions:

• chr10-101010757-T-C
• chr10-101010757-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001195263.2(PDZD7):​c.2132A>G​(p.His711Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.033 in 1,319,644 control chromosomes in the GnomAD database, including 720 homozygotes. In-silico tool predicts a benign outcome for this variant. 8/12 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.029 (82 hom., cov: 30)
  • Exomes 𝑓: 0.033 (638 hom.)
• Consequence: PDZD7 NM_001195263.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.42

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002282381).
• BP6: Variant 10-101010757-T-C is Benign according to our data. Variant chr10-101010757-T-C is described in ClinVar as [Benign]. Clinvar id is 44122.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0295 (4119/139684) while in subpopulation AFR AF= 0.0357 (1342/37610). AF 95% confidence interval is 0.0341. There are 82 homozygotes in gnomad4. There are 1978 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 82 AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PDZD7	NM_001195263.2	c.2132A>G	p.His711Arg	missense_variant	15/17	ENST00000619208.6	NP_001182192.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PDZD7	ENST00000619208.6	c.2132A>G	p.His711Arg	missense_variant	15/17	5	NM_001195263.2	ENSP00000480489	P1
PDZD7	ENST00000474125.7	c.*2079A>G		3_prime_UTR_variant, NMD_transcript_variant	11/13	2		ENSP00000474447

Frequencies

GnomAD3 genomes AF: 0.0294 AC: 4110 AN: 139592 Hom.: 81 Cov.: 30

Gnomad AFR AF: 0.0356

Gnomad AMI AF: 0.0144

Gnomad AMR AF: 0.0196

Gnomad ASJ AF: 0.0603

Gnomad EAS AF: 0.000223

Gnomad SAS AF: 0.0253

Gnomad FIN AF: 0.0486

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0262

Gnomad OTH AF: 0.0369

GnomAD3 exomes AF: 0.0256 AC: 3330 AN: 130090 Hom.: 61 AF XY: 0.0259 AC XY: 1845 AN XY: 71284

Gnomad AFR exome AF: 0.0362

Gnomad AMR exome AF: 0.0160

Gnomad ASJ exome AF: 0.0524

Gnomad EAS exome AF: 0.0000958

Gnomad SAS exome AF: 0.0270

Gnomad FIN exome AF: 0.0504

Gnomad NFE exome AF: 0.0265

Gnomad OTH exome AF: 0.0272

GnomAD4 exome AF: 0.0334 AC: 39455 AN: 1179960 Hom.: 638 Cov.: 45 AF XY: 0.0333 AC XY: 19370 AN XY: 581500

Gnomad4 AFR exome AF: 0.0432

Gnomad4 AMR exome AF: 0.0191

Gnomad4 ASJ exome AF: 0.0685

Gnomad4 EAS exome AF: 0.000173

Gnomad4 SAS exome AF: 0.0275

Gnomad4 FIN exome AF: 0.0877

Gnomad4 NFE exome AF: 0.0329

Gnomad4 OTH exome AF: 0.0348

GnomAD4 genome AF: 0.0295 AC: 4119 AN: 139684 Hom.: 82 Cov.: 30 AF XY: 0.0292 AC XY: 1978 AN XY: 67834

Gnomad4 AFR AF: 0.0357

Gnomad4 AMR AF: 0.0195

Gnomad4 ASJ AF: 0.0603

Gnomad4 EAS AF: 0.000223

Gnomad4 SAS AF: 0.0253

Gnomad4 FIN AF: 0.0486

Gnomad4 NFE AF: 0.0262

Gnomad4 OTH AF: 0.0365

Alfa AF: 0.0272 Hom.: 13

Bravo AF: 0.0266

TwinsUK AF: 0.0302 AC: 112

ALSPAC AF: 0.0278 AC: 107

ExAC AF: 0.0184 AC: 400

Asia WGS AF: 0.0140 AC: 47 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 29, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 09, 2019	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 19, 2013	His711Arg in exon 15 of PDZD7: This variant is not expected to have clinical sig nificance because it has been identified in 2.7% (59/2178) of chromosomes from a broad population from the 1000 Genomes project (http://www.ncbi.nlm.nih.gov/var iation/tools/1000genomes; rs34616847). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	15
DANN	Benign	0.79
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.26
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.46	.;T
MetaRNN	Benign	0.0023	T;T
MetaSVM	Benign	-1.0	T
PrimateAI	Uncertain	0.52	T
Sift4G	Benign	0.37	.;T
Vest4		0.057
ClinPred		0.054	T
GERP RS		3.7
Varity_R		0.11
gMVP		0.21

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs34616847; hg19: chr10-102770514; COSMIC: COSV64651828; COSMIC: COSV64651828;