3-102438490-G-A

Position:

• chr3-102438490-G-A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_001329788.2(ZPLD1):​c.3G>A​(p.Met1?) variant causes a start lost 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 start_lost
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.79

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 Pathogenic. Variant got 10 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZPLD1	NM_001329788.2	c.3G>A	p.Met1?	start_lost	3/12	ENST00000466937.2	NP_001316717.1
ZPLD1	XM_017005703.1	c.3G>A	p.Met1?	start_lost	3/12		XP_016861192.1
ZPLD1	XM_017005704.1	c.3G>A	p.Met1?	start_lost	2/11		XP_016861193.1
ZPLD1	NM_175056.2	c.51G>A	p.Met17Ile	missense_variant	2/11		NP_778226.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZPLD1	ENST00000466937.2	c.3G>A	p.Met1?	start_lost	3/12	1	NM_001329788.2	ENSP00000418253.1
ZPLD1	ENST00000491959.5	c.3G>A	p.Met1?	start_lost	9/18	1		ENSP00000420265.1
ZPLD1	ENST00000306176.5	c.51G>A	p.Met17Ile	missense_variant	2/11	1		ENSP00000307801.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

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

Feb 12, 2024

The c.51G>A (p.M17I) alteration is located in exon 2 (coding exon 2) of the ZPLD1 gene. This alteration results from a G to A substitution at nucleotide position 51, causing the methionine (M) at amino acid position 17 to be replaced by an isoleucine (I). 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
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.034	T;.;T
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.56	.;T;D
M_CAP	Pathogenic	0.57	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Uncertain	0.58	D
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-1.2	N;N;N
REVEL	Pathogenic	0.79
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		0.85	P;P;P
Vest4		0.86
MutPred		0.94		Gain of catalytic residue at M1 (P = 0.0208);.;Gain of catalytic residue at M1 (P = 0.0208);
MVP		0.81
MPC		0.22
ClinPred		0.99	D
GERP RS		5.1
Varity_R		0.84
gMVP		0.74

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-102157334;