3-102469122-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001329788.2(ZPLD1):c.920C>A(p.Pro307His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,458,540 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: ZPLD1 NM_001329788.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.23

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.25909877).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZPLD1	NM_001329788.2	c.920C>A	p.Pro307His	missense_variant	9/12	ENST00000466937.2
ZPLD1	NM_175056.2	c.968C>A	p.Pro323His	missense_variant	8/11
ZPLD1	XM_017005703.1	c.920C>A	p.Pro307His	missense_variant	9/12
ZPLD1	XM_017005704.1	c.920C>A	p.Pro307His	missense_variant	8/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZPLD1	ENST00000466937.2	c.920C>A	p.Pro307His	missense_variant	9/12	1	NM_001329788.2	P1
ZPLD1	ENST00000306176.5	c.968C>A	p.Pro323His	missense_variant	8/11	1
ZPLD1	ENST00000491959.5	c.920C>A	p.Pro307His	missense_variant	15/18	1		P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1458540 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 725494

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: 9.00e-7

Gnomad4 OTH exome AF: 0.00

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

Jan 04, 2024

The c.968C>A (p.P323H) alteration is located in exon 8 (coding exon 8) of the ZPLD1 gene. This alteration results from a C to A substitution at nucleotide position 968, causing the proline (P) at amino acid position 323 to be replaced by a histidine (H). 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	Benign	0.14
BayesDel_addAF	Uncertain	0.030	T
BayesDel_noAF	Benign	-0.19
Cadd	Benign	22
Dann	Benign	0.96
DEOGEN2	Benign	0.012	T;.;T
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.17
FATHMM_MKL	Uncertain	0.94	D
M_CAP	Benign	0.041	D
MetaRNN	Benign	0.26	T;T;T
MetaSVM	Benign	-0.51	T
MutationAssessor	Uncertain	2.2	M;.;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-1.6	N;N;N
REVEL	Benign	0.26
Sift	Benign	0.10	T;T;T
Sift4G	Benign	0.25	T;T;T
Polyphen		0.019	B;B;B
Vest4		0.53
MutPred		0.44		Loss of sheet (P = 0.0817);.;Loss of sheet (P = 0.0817);
MVP		0.70
MPC		0.088
ClinPred		0.35	T
GERP RS		4.6
Varity_R		0.17
gMVP		0.42

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: chr3-102187966;