rs1554834161

Positions:

• chr10-101015737-G-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001195263.2(PDZD7):​c.1648C>T​(p.Gln550Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000215 in 1,397,926 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: PDZD7 NM_001195263.2 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 3.93

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 Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 10-101015737-G-A is Pathogenic according to our data. Variant chr10-101015737-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 545404.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-101015737-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PDZD7	NM_001195263.2	c.1648C>T	p.Gln550Ter	stop_gained	11/17	ENST00000619208.6	NP_001182192.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PDZD7	ENST00000619208.6	c.1648C>T	p.Gln550Ter	stop_gained	11/17	5	NM_001195263.2	ENSP00000480489	P1
PDZD7	ENST00000644782.1	c.1522+2362C>T		intron_variant				ENSP00000496747
PDZD7	ENST00000474125.7	c.*1700+2362C>T		intron_variant, NMD_transcript_variant		2		ENSP00000474447

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000215 AC: 3 AN: 1397926 Hom.: 0 Cov.: 34 AF XY: 0.00000145 AC XY: 1 AN XY: 689500

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000252

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.27e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hearing loss, autosomal recessive 57 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jun 23, 2023	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 2010	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Oct 01, 2023

PDZD7: PVS1, PM2, PM3 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.75
CADD	Pathogenic	35
DANN	Uncertain	0.99
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.42
FATHMM_MKL	Benign	0.20	N
Vest4		0.026
GERP RS		3.2

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1554834161; hg19: chr10-102775494;