3-102456362-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001329788.2(ZPLD1):c.497C>A(p.Thr166Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,457,640 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: ZPLD1 NM_001329788.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.55

Genes affected

ZPLD1 (HGNC:27022): (zona pellucida like domain containing 1) Predicted to be an extracellular matrix structural constituent. Predicted to act upstream of or within vestibular reflex. Predicted to be located in cytoplasmic vesicle membrane. Predicted to be integral component of membrane. Predicted to be active in cell surface and extracellular space. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.856

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZPLD1	NM_001329788.2	c.497C>A	p.Thr166Asn	missense_variant	5/12	ENST00000466937.2
ZPLD1	NM_175056.2	c.545C>A	p.Thr182Asn	missense_variant	4/11
ZPLD1	XM_017005703.1	c.497C>A	p.Thr166Asn	missense_variant	5/12
ZPLD1	XM_017005704.1	c.497C>A	p.Thr166Asn	missense_variant	4/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZPLD1	ENST00000466937.2	c.497C>A	p.Thr166Asn	missense_variant	5/12	1	NM_001329788.2	P1
ZPLD1	ENST00000306176.5	c.545C>A	p.Thr182Asn	missense_variant	4/11	1
ZPLD1	ENST00000491959.5	c.497C>A	p.Thr166Asn	missense_variant	11/18	1		P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1457640 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 724970

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: 0.00000180

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 09, 2022

The c.545C>A (p.T182N) alteration is located in exon 4 (coding exon 4) of the ZPLD1 gene. This alteration results from a C to A substitution at nucleotide position 545, causing the threonine (T) at amino acid position 182 to be replaced by an asparagine (N). 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	Uncertain	0.44
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
Cadd	Pathogenic	27
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.46	T;.;T
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Benign	0.053	D
MetaRNN	Pathogenic	0.86	D;D;D
MetaSVM	Uncertain	0.29	D
MutationAssessor	Uncertain	2.6	M;.;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-3.0	D;D;D
REVEL	Uncertain	0.62
Sift	Uncertain	0.0050	D;D;D
Sift4G	Uncertain	0.013	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.86
MutPred		0.60		Loss of sheet (P = 0.0457);.;Loss of sheet (P = 0.0457);
MVP		0.81
MPC		0.45
ClinPred		0.98	D
GERP RS		5.7
Varity_R		0.63
gMVP		0.58

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1707413367; hg19: chr3-102175206;