10-101008496-T-C

Position:

• chr10-101008496-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001195263.2(PDZD7):​c.3073A>G​(p.Lys1025Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000653 in 1,377,666 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000065 (0 hom.)
• Consequence: PDZD7 NM_001195263.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -0.861

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07451782).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PDZD7	NM_001195263.2	c.3073A>G	p.Lys1025Glu	missense_variant	17/17	ENST00000619208.6	NP_001182192.1
PDZD7	XM_011540177.4	c.3073A>G	p.Lys1025Glu	missense_variant	18/18		XP_011538479.1
PDZD7	XM_047425767.1	c.3073A>G	p.Lys1025Glu	missense_variant	17/17		XP_047281723.1
PDZD7	XM_011540178.4	c.3070A>G	p.Lys1024Glu	missense_variant	17/17		XP_011538480.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PDZD7	ENST00000619208.6	c.3073A>G	p.Lys1025Glu	missense_variant	17/17	5	NM_001195263.2	ENSP00000480489.1
PDZD7	ENST00000474125.7	n.*3020A>G		non_coding_transcript_exon_variant	13/13	2		ENSP00000474447.1
PDZD7	ENST00000474125.7	n.*3020A>G		3_prime_UTR_variant	13/13	2		ENSP00000474447.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 0.00000653 AC: 9 AN: 1377666 Hom.: 0 Cov.: 32 AF XY: 0.00000736 AC XY: 5 AN XY: 678984

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000744

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 30

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 14, 2022	This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 1025 of the PDZD7 protein (p.Lys1025Glu). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with PDZD7-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0"). 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. -
Uncertain significance, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	0.70
DANN	Benign	0.48
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.083	N
LIST_S2	Benign	0.35	.;T
MetaRNN	Benign	0.075	T;T
MetaSVM	Benign	-0.99	T
PrimateAI	Benign	0.33	T
Sift4G	Benign	0.89	.;T
Vest4		0.099
MVP		0.043
ClinPred		0.066	T
GERP RS		-1.1
Varity_R		0.053
gMVP		0.15

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs772312008; hg19: chr10-102768253;