3-102456248-G-A

Position:

• chr3-102456248-G-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.383G>A​(p.Gly128Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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)
• Consequence: ZPLD1 NM_001329788.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.58

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, 0.875

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZPLD1	NM_001329788.2	c.383G>A	p.Gly128Glu	missense_variant	5/12	ENST00000466937.2	NP_001316717.1
ZPLD1	NM_175056.2	c.431G>A	p.Gly144Glu	missense_variant	4/11		NP_778226.1
ZPLD1	XM_017005703.1	c.383G>A	p.Gly128Glu	missense_variant	5/12		XP_016861192.1
ZPLD1	XM_017005704.1	c.383G>A	p.Gly128Glu	missense_variant	4/11		XP_016861193.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZPLD1	ENST00000466937.2	c.383G>A	p.Gly128Glu	missense_variant	5/12	1	NM_001329788.2	ENSP00000418253.1
ZPLD1	ENST00000306176.5	c.431G>A	p.Gly144Glu	missense_variant	4/11	1		ENSP00000307801.1
ZPLD1	ENST00000491959.5	c.383G>A	p.Gly128Glu	missense_variant	11/18	1		ENSP00000420265.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

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

Sep 12, 2023

The c.431G>A (p.G144E) alteration is located in exon 4 (coding exon 4) of the ZPLD1 gene. This alteration results from a G to A substitution at nucleotide position 431, causing the glycine (G) at amino acid position 144 to be replaced by a glutamic acid (E). 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	0.98
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.26
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.24	T;.;T
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.94	.;D;D
M_CAP	Uncertain	0.23	D
MetaRNN	Pathogenic	0.87	D;D;D
MetaSVM	Uncertain	-0.18	T
MutationAssessor	Benign	1.9	M;.;M
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-1.3	N;N;N
REVEL	Pathogenic	0.70
Sift	Benign	0.12	T;T;T
Sift4G	Uncertain	0.043	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.92
MutPred		0.59		Gain of loop (P = 0.0435);.;Gain of loop (P = 0.0435);
MVP		0.89
MPC		0.45
ClinPred		0.99	D
GERP RS		5.5
Varity_R		0.47
gMVP		0.84

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

LitVar

Other links and lift over

dbSNP: rs149996665; hg19: chr3-102175092; COSMIC: COSV60353701;