3-102453094-T-A

Variant names:

• chr3-102453094-T-A
• NM_001329788.2:c.282T>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.282T>A​(p.Phe94Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,822 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: ZPLD1 NM_001329788.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.383

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, 0.915

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZPLD1	NM_001329788.2	c.282T>A	p.Phe94Leu	missense_variant	Exon 4 of 12	ENST00000466937.2	NP_001316717.1
ZPLD1	NM_175056.2	c.330T>A	p.Phe110Leu	missense_variant	Exon 3 of 11		NP_778226.1
ZPLD1	XM_017005703.1	c.282T>A	p.Phe94Leu	missense_variant	Exon 4 of 12		XP_016861192.1
ZPLD1	XM_017005704.1	c.282T>A	p.Phe94Leu	missense_variant	Exon 3 of 11		XP_016861193.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZPLD1	ENST00000466937.2	c.282T>A	p.Phe94Leu	missense_variant	Exon 4 of 12	1	NM_001329788.2	ENSP00000418253.1
ZPLD1	ENST00000306176.5	c.330T>A	p.Phe110Leu	missense_variant	Exon 3 of 11	1		ENSP00000307801.1
ZPLD1	ENST00000491959.5	c.282T>A	p.Phe94Leu	missense_variant	Exon 10 of 18	1		ENSP00000420265.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461822 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727208

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: 0.00000360

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome Cov.: 32

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 08, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.330T>A (p.F110L) alteration is located in exon 3 (coding exon 3) of the ZPLD1 gene. This alteration results from a T to A substitution at nucleotide position 330, causing the phenylalanine (F) at amino acid position 110 to be replaced by a leucine (L). 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	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.34	T;.;T
Eigen	Benign	0.18
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.87	.;D;D
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.92	D;D;D
MetaSVM	Uncertain	0.083	D
MutationAssessor	Uncertain	2.7	M;.;M
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-2.4	N;N;N
REVEL	Pathogenic	0.70
Sift	Uncertain	0.0070	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.92
MutPred		0.73		Gain of sheet (P = 0.0221);.;Gain of sheet (P = 0.0221);
MVP		0.89
MPC		0.46
ClinPred		0.97	D
GERP RS		2.2
Varity_R		0.42
gMVP		0.83

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-102171938;