X-153804063-G-C

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001303512.2(PDZD4):​c.1618C>G​(p.Pro540Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000879 in 113,744 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. 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. P540S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000088 (0 hom., 1 hem., cov: 25)
  • Exomes 𝑓: 0.0000029 (0 hom. 2 hem.)
  • Failed GnomAD Quality Control
• Consequence: PDZD4 NM_001303512.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.00
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.053558588).

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.1618C>G	p.Pro540Ala	missense	Exon 8 of 8	NP_001290441.1	Q17RL8
	PDZD4	NM_032512.5		c.1600C>G	p.Pro534Ala	missense	Exon 8 of 8	NP_115901.2
	PDZD4	NM_001303515.2		c.1375C>G	p.Pro459Ala	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.1618C>G	p.Pro540Ala	missense	Exon 8 of 8	ENSP00000377355.3	Q17RL8
	PDZD4	ENST00000164640.8	TSL:1	c.1600C>G	p.Pro534Ala	missense	Exon 8 of 8	ENSP00000164640.4	Q76G19-1
	PDZD4	ENST00000544474.5	TSL:1	c.1273C>G	p.Pro425Ala	missense	Exon 6 of 6	ENSP00000442033.1	Q76G19-2

Frequencies

GnomAD3 genomes AF: 0.00000879 AC: 1 AN: 113744 Hom.: 0 Cov.: 25

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000187

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000215 AC: 2 AN: 92867 AF XY: 0.0000313

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000595

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000287 AC: 3 AN: 1044160 Hom.: 0 Cov.: 33 AF XY: 0.00000588 AC XY: 2 AN XY: 339990

African (AFR) AF: 0.00 AC: 0 AN: 24817

American (AMR) AF: 0.00 AC: 0 AN: 27550

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18441

East Asian (EAS) AF: 0.00 AC: 0 AN: 27077

South Asian (SAS) AF: 0.00 AC: 0 AN: 49363

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 30672

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3790

European-Non Finnish (NFE) AF: 0.00000244 AC: 2 AN: 818314

Other (OTH) AF: 0.0000227 AC: 1 AN: 44136

GnomAD4 genome AF: 0.00000879 AC: 1 AN: 113744 Hom.: 0 Cov.: 25 AF XY: 0.0000279 AC XY: 1 AN XY: 35876

African (AFR) AF: 0.00 AC: 0 AN: 31441

American (AMR) AF: 0.00 AC: 0 AN: 10924

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2664

East Asian (EAS) AF: 0.00 AC: 0 AN: 3588

South Asian (SAS) AF: 0.00 AC: 0 AN: 2869

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 239

European-Non Finnish (NFE) AF: 0.0000187 AC: 1 AN: 53384

Other (OTH) AF: 0.00 AC: 0 AN: 1541

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.054
BayesDel_addAF	Benign	-0.74	T
BayesDel_noAF	Benign	-1.1
CADD	Benign	0.25
DANN	Benign	0.27
DEOGEN2	Benign	0.14	T
FATHMM_MKL	Benign	0.038	N
LIST_S2	Benign	0.58	T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.054	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.42	N
PhyloP100		-1.0
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-0.87	N
REVEL	Benign	0.016
Sift	Benign	0.27	T
Sift4G	Benign	0.40	T
Polyphen		0.0	B
Vest4		0.076
MutPred		0.17		Loss of loop (P = 0.0374)
MVP		0.082
MPC		0.87
ClinPred		0.027	T
GERP RS		0.49
Varity_R		0.042
gMVP		0.32
Mutation Taster		=100/0	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: rs892206256; hg19: chrX-153069518;