X-153804125-G-T

Variant names:

• chrX-153804125-G-T
• rs1458304851
• NM_001303512.2:c.1556C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001303512.2(PDZD4):​c.1556C>A​(p.Thr519Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000965 in 1,036,729 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T519I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 26)
  • Exomes 𝑓: 9.6e-7 (0 hom. 0 hem.)
• Consequence: PDZD4 NM_001303512.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.536
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08917609).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001303512.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDZD4	NM_001303512.2	MANE Select	c.1556C>A	p.Thr519Asn	missense	Exon 8 of 8	NP_001290441.1	Q17RL8
	PDZD4	NM_032512.5		c.1538C>A	p.Thr513Asn	missense	Exon 8 of 8	NP_115901.2
	PDZD4	NM_001303515.2		c.1313C>A	p.Thr438Asn	missense	Exon 8 of 8	NP_001290444.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDZD4	ENST00000393758.7	TSL:1 MANE Select	c.1556C>A	p.Thr519Asn	missense	Exon 8 of 8	ENSP00000377355.3	Q17RL8
	PDZD4	ENST00000164640.8	TSL:1	c.1538C>A	p.Thr513Asn	missense	Exon 8 of 8	ENSP00000164640.4	Q76G19-1
	PDZD4	ENST00000544474.5	TSL:1	c.1211C>A	p.Thr404Asn	missense	Exon 6 of 6	ENSP00000442033.1	Q76G19-2

Frequencies

GnomAD3 genomes Cov.: 26

GnomAD4 exome AF: 9.65e-7 AC: 1 AN: 1036729 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 333785

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 24819

American (AMR) AF: 0.00 AC: 0 AN: 27043

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18013

East Asian (EAS) AF: 0.00 AC: 0 AN: 27118

South Asian (SAS) AF: 0.00 AC: 0 AN: 48268

European-Finnish (FIN) AF: 0.0000344 AC: 1 AN: 29072

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3689

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 814864

Other (OTH) AF: 0.00 AC: 0 AN: 43843

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 26

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-1.1
CADD	Benign	1.4
DANN	Benign	0.37
DEOGEN2	Benign	0.097	T
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.69	T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.089	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.75	N
PhyloP100		0.54
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.15	N
REVEL	Benign	0.011
Sift	Benign	0.30	T
Sift4G	Benign	0.52	T
Polyphen		0.0	B
Vest4		0.062
MutPred		0.16		Loss of phosphorylation at T513 (P = 0.0017)
MVP		0.20
MPC		1.0
ClinPred		0.24	T
GERP RS		1.6
Varity_R		0.046
gMVP		0.29
Mutation Taster		=94/6	polymorphism

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

Other links and lift over

dbSNP: rs1458304851; hg19: chrX-153069580;