3-102470398-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001329788.2(ZPLD1):c.938G>A(p.Cys313Tyr) 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: 9.45

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.993

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZPLD1	NM_001329788.2	c.938G>A	p.Cys313Tyr	missense_variant	10/12	ENST00000466937.2
ZPLD1	NM_175056.2	c.986G>A	p.Cys329Tyr	missense_variant	9/11
ZPLD1	XM_017005703.1	c.938G>A	p.Cys313Tyr	missense_variant	10/12
ZPLD1	XM_017005704.1	c.938G>A	p.Cys313Tyr	missense_variant	9/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZPLD1	ENST00000466937.2	c.938G>A	p.Cys313Tyr	missense_variant	10/12	1	NM_001329788.2	P1
ZPLD1	ENST00000306176.5	c.986G>A	p.Cys329Tyr	missense_variant	9/11	1
ZPLD1	ENST00000491959.5	c.938G>A	p.Cys313Tyr	missense_variant	16/18	1		P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

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

Nov 30, 2022

The c.986G>A (p.C329Y) alteration is located in exon 9 (coding exon 9) of the ZPLD1 gene. This alteration results from a G to A substitution at nucleotide position 986, causing the cysteine (C) at amino acid position 329 to be replaced by a tyrosine (Y). 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	0.45	D
BayesDel_noAF	Pathogenic	0.41
Cadd	Pathogenic	29
Dann	Uncertain	1.0
DEOGEN2	Benign	0.41	T;.;T
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	1.0	D
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Uncertain	0.79	D
MutationAssessor	Uncertain	2.6	M;.;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-9.2	D;D;D
REVEL	Pathogenic	0.87
Sift	Pathogenic	0.0	D;D;D
Sift4G	Uncertain	0.0080	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.99
MutPred		0.96		Gain of loop (P = 0.0502);.;Gain of loop (P = 0.0502);
MVP		0.91
MPC		0.55
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.97
gMVP		0.93

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: chr3-102189242;