10-101008477-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001195263.2(PDZD7):c.3092G>A(p.Arg1031His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0508 in 1,498,056 control chromosomes in the GnomAD database, including 2,318 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 Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1031C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.039 (153 hom., cov: 30)
  • Exomes 𝑓: 0.052 (2165 hom.)
• Consequence: PDZD7 NM_001195263.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• 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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017986596).
• BP6: Variant 10-101008477-C-T is Benign according to our data. Variant chr10-101008477-C-T is described in ClinVar as [Benign]. Clinvar id is 194723.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.056 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PDZD7	NM_001195263.2	c.3092G>A	p.Arg1031His	missense_variant	17/17	ENST00000619208.6
PDZD7	XM_011540177.4	c.3092G>A	p.Arg1031His	missense_variant	18/18
PDZD7	XM_047425767.1	c.3092G>A	p.Arg1031His	missense_variant	17/17
PDZD7	XM_011540178.4	c.3089G>A	p.Arg1030His	missense_variant	17/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PDZD7	ENST00000619208.6	c.3092G>A	p.Arg1031His	missense_variant	17/17	5	NM_001195263.2	P1
PDZD7	ENST00000474125.7	c.*3039G>A		3_prime_UTR_variant, NMD_transcript_variant	13/13	2

Frequencies

GnomAD3 genomes AF: 0.0386 AC: 5410 AN: 140272 Hom.: 153 Cov.: 30

Gnomad AFR AF: 0.0125

Gnomad AMI AF: 0.00355

Gnomad AMR AF: 0.0354

Gnomad ASJ AF: 0.0268

Gnomad EAS AF: 0.00167

Gnomad SAS AF: 0.0613

Gnomad FIN AF: 0.0280

Gnomad MID AF: 0.0641

Gnomad NFE AF: 0.0573

Gnomad OTH AF: 0.0399

GnomAD3 exomes AF: 0.0406 AC: 4976 AN: 122554 Hom.: 148 AF XY: 0.0435 AC XY: 2829 AN XY: 65108

Gnomad AFR exome AF: 0.0104

Gnomad AMR exome AF: 0.0207

Gnomad ASJ exome AF: 0.0288

Gnomad EAS exome AF: 0.000826

Gnomad SAS exome AF: 0.0663

Gnomad FIN exome AF: 0.0280

Gnomad NFE exome AF: 0.0561

Gnomad OTH exome AF: 0.0446

GnomAD4 exome AF: 0.0521 AC: 70756 AN: 1357696 Hom.: 2165 Cov.: 32 AF XY: 0.0524 AC XY: 34972 AN XY: 666814

Gnomad4 AFR exome AF: 0.00924

Gnomad4 AMR exome AF: 0.0217

Gnomad4 ASJ exome AF: 0.0291

Gnomad4 EAS exome AF: 0.000706

Gnomad4 SAS exome AF: 0.0644

Gnomad4 FIN exome AF: 0.0266

Gnomad4 NFE exome AF: 0.0566

Gnomad4 OTH exome AF: 0.0485

GnomAD4 genome AF: 0.0386 AC: 5411 AN: 140360 Hom.: 153 Cov.: 30 AF XY: 0.0379 AC XY: 2572 AN XY: 67822

Gnomad4 AFR AF: 0.0126

Gnomad4 AMR AF: 0.0354

Gnomad4 ASJ AF: 0.0268

Gnomad4 EAS AF: 0.00167

Gnomad4 SAS AF: 0.0621

Gnomad4 FIN AF: 0.0280

Gnomad4 NFE AF: 0.0573

Gnomad4 OTH AF: 0.0385

Alfa AF: 0.0522 Hom.: 292

Bravo AF: 0.0347

TwinsUK AF: 0.0569 AC: 211

ALSPAC AF: 0.0594 AC: 229

ExAC AF: 0.0288 AC: 853

Asia WGS AF: 0.0220 AC: 76 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 27, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 28, 2018	p.Arg1031His in Exon 17 of PDZD7: This variant is not expected to have clinical significance because it has also been identified in 7% (50/18610) South Asian ch romosomes and 5% (100/59384) European chromosomes by the Genome Aggregation Data base (gnomAD, http://gnomad.broadinstitute.org). rs72838683). ACMG/AMP criteria applied: BA1. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 05, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.53
Cadd	Benign	0.070
Dann	Benign	0.75
Eigen	Benign	-1.8
Eigen_PC	Benign	-2.0
FATHMM_MKL	Benign	0.017	N
MetaRNN	Benign	0.0018	T;T
MetaSVM	Benign	-0.99	T
PrimateAI	Benign	0.22	T
Vest4		0.074
ClinPred		0.014	T
GERP RS		-9.3
Varity_R		0.017
gMVP		0.14

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs72838683; hg19: chr10-102768234;