chrX:153803771:1:A

You've typed an SPDI variant (sequence:position:deletion:insertion), where the position is zero-based, unlike in chromosome-position-reference-alternate.

Variant names:

• chrX-153803772-C-A
• NM_001303512.2:c.1909G>T
• PDZD4 p.Asp637Tyr

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+3 Uncertain · Warm

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 3 classification points (ACMG Germline Pathogenicity v2019). PM2PP3

The NM_001303512.2(PDZD4):c.1909G>T (p.Asp637Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. In-silico predictor (REVEL) classifies this variant as likely damaging/oncogenic. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 25)
• Consequence: PDZD4 NM_001303512.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.10
• 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]

Classification according to ACMG Germline Pathogenicity v2019

Our verdict: Uncertain_significance. The variant received 3 points.

• PM2: Absent from gnomAD (AR/unknown gene) — PM2; Absent from gnomAD at well-covered site (MOI: unknown) (threshold 0.001) — PM2 moderate.
• PP3: Germline meta computational scorer (REVEL/MetaRNN/BayesDel) predicts damaging effect — supporting evidence (PP3); Splicing verdict: not pathogenic.; Germline computational verdict: pathogenic (Supporting).

Variant Effect in Transcripts

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

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDZD4	NM_001303512.2	MANE Select	c.1909G>T	p.Asp637Tyr	missense	Exon 8 of 8	NP_001290441.1	F6S393
	PDZD4	NM_032512.5		c.1891G>T	p.Asp631Tyr	missense	Exon 8 of 8	NP_115901.2
	PDZD4	NM_001303515.2		c.1666G>T	p.Asp556Tyr	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.1909G>T	p.Asp637Tyr	missense	Exon 8 of 8	ENSP00000377355.3	F6S393
	PDZD4	ENST00000164640.8	TSL:1	c.1891G>T	p.Asp631Tyr	missense	Exon 8 of 8	ENSP00000164640.4	Q76G19-1
	PDZD4	ENST00000544474.5	TSL:1	c.1564G>T	p.Asp522Tyr	missense	Exon 6 of 6	ENSP00000442033.1	Q76G19-2

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 3 sources Large-scale international reference populations
GnomAD3 genomes					25
GnomAD4 exome					33
GnomAD4 genome					25

Showing 3 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated prediction	Prediction	Score
AlphaGenome AVI	Pathogenic	-	27
AlphaMissense	Pathogenic	-	1.0
BayesDel_addAF	Pathogenic	D	0.34
BayesDel_noAF	Pathogenic	-	0.25
CADD	Pathogenic	-	26
DANN	Uncertain	-	0.99
DEOGEN2	Pathogenic	D	0.80
FATHMM_MKL	Pathogenic	D	1.0
FuncVEP CTI	Pathogenic	-	0.99
GPN-Star LLR	N/A	-	-9.8
GPN-Star score	N/A	-	9.8
LIST_S2	Pathogenic	D	1.0
M_CAP	Pathogenic	D	0.60
MetaRNN	Pathogenic	D	0.87
MetaSVM	Uncertain	T	-0.15
Mutation Taster	N/A	disease causing	31/69
MutationAssessor	Uncertain	M	2.7
PhyloP100	Uncertain	-	6.1
popEVE	Benign	-	-4.6
PrimateAI	Pathogenic	D	0.86
PROVEAN	Pathogenic	D	-8.7
REVEL	Pathogenic	-	0.67
Sift	Pathogenic	D	0.0
Sift4G	Pathogenic	D	0.0
Varity_R	N/A	-	0.97
VESM-3B	Benign	-	-15

Showing 26 of 26 scores

Splicing Scores

Algorithm	Calibrated prediction	Prediction	Score
Pangolin (max)	Benign	-	0.0
SpliceAI score (max)	Benign	- Details are displayed if max score is > 0.2	0.0

Showing 2 of 2 scores

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chrX-153069227;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar