X-153804063-G-A

Variant names:

• chrX-153804063-G-A
• rs892206256
• NM_001303512.2:c.1618C>T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001303512.2(PDZD4):​c.1618C>T​(p.Pro540Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000287 in 1,044,160 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 25)
  • Exomes 𝑓: 0.0000029 (0 hom. 1 hem.)
• Consequence: PDZD4 NM_001303512.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.00

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.049129397).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PDZD4	NM_001303512.2	c.1618C>T	p.Pro540Ser	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.1618C>T	p.Pro540Ser	missense_variant	Exon 8 of 8	1	NM_001303512.2	ENSP00000377355.3
PDZD4	ENST00000164640.8	c.1600C>T	p.Pro534Ser	missense_variant	Exon 8 of 8	1		ENSP00000164640.4
PDZD4	ENST00000544474.5	c.1273C>T	p.Pro425Ser	missense_variant	Exon 6 of 6	1		ENSP00000442033.1

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD4 exome AF: 0.00000287 AC: 3 AN: 1044160 Hom.: 0 Cov.: 33 AF XY: 0.00000294 AC XY: 1 AN XY: 339990

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000363

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: 0.00000244

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 25

Bravo AF: 0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 12, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1600C>T (p.P534S) alteration is located in exon 8 (coding exon 8) of the PDZD4 gene. This alteration results from a C to T substitution at nucleotide position 1600, causing the proline (P) at amino acid position 534 to be replaced by a serine (S). 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	0.071
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-1.1
CADD	Benign	0.20
DANN	Benign	0.43
DEOGEN2	Benign	0.11	T;.;T
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.59	T;T;T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.049	T;T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.42	N;.;.
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.84	N;N;.
REVEL	Benign	0.014
Sift	Benign	0.33	T;T;.
Sift4G	Benign	0.48	T;T;T
Polyphen		0.0	B;.;B
Vest4		0.021
MutPred		0.19		Gain of phosphorylation at P534 (P = 0.003);.;.;
MVP		0.093
MPC		0.90
ClinPred		0.13	T
GERP RS		0.49
Varity_R		0.048
gMVP		0.37

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: rs892206256; hg19: chrX-153069518;