X-153803954-C-A

Variant names:

• chrX-153803954-C-A
• rs2092194198
• NM_001303512.2:c.1727G>T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001303512.2(PDZD4):​c.1727G>T​(p.Arg576Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 26)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: PDZD4 NM_001303512.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.59

Genes affected

PDZD4 (HGNC:21167): (PDZ domain containing 4) Predicted to be located in cell cortex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.26822504).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PDZD4	NM_001303512.2	c.1727G>T	p.Arg576Leu	missense_variant	Exon 8 of 8	ENST00000393758.7	NP_001290441.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PDZD4	ENST00000393758.7	c.1727G>T	p.Arg576Leu	missense_variant	Exon 8 of 8	1	NM_001303512.2	ENSP00000377355.3
PDZD4	ENST00000164640.8	c.1709G>T	p.Arg570Leu	missense_variant	Exon 8 of 8	1		ENSP00000164640.4
PDZD4	ENST00000544474.5	c.1382G>T	p.Arg461Leu	missense_variant	Exon 6 of 6	1		ENSP00000442033.1

Frequencies

GnomAD3 genomes Cov.: 26

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1049856 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 340456

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 26

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 21, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1709G>T (p.R570L) alteration is located in exon 8 (coding exon 8) of the PDZD4 gene. This alteration results from a G to T substitution at nucleotide position 1709, causing the arginine (R) at amino acid position 570 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.33	T;.;T
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.68	T;T;T
M_CAP	Benign	0.060	D
MetaRNN	Benign	0.27	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.3	M;.;.
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-3.1	D;D;.
REVEL	Benign	0.13
Sift	Benign	0.061	T;T;.
Sift4G	Benign	0.20	T;T;T
Polyphen		0.96	D;.;P
Vest4		0.37
MutPred		0.23		Loss of MoRF binding (P = 0.0487);.;.;
MVP		0.28
MPC		1.9
ClinPred		0.97	D
GERP RS		3.8
Varity_R		0.48
gMVP		0.75

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs2092194198; hg19: chrX-153069409;