Genetic Variant ZPLD1:p.Asn129Ser (chr3-102456251-A-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_001329788.2(ZPLD1):c.386A>G(p.Asn129Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000105 in 1,613,636 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000010 ( 0 hom. )

Consequence

ZPLD1
NM_001329788.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.08

Variant links:

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]

ZPLD1 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZPLD1	NM_001329788.2 link	c.386A>G	p.Asn129Ser	missense_variant	Exon 5 of 12	ENST00000466937.2	NP_001316717.1	Q8TCW7-1
ZPLD1	NM_175056.2 link	c.434A>G	p.Asn145Ser	missense_variant	Exon 4 of 11		NP_778226.1	Q8TCW7-2
ZPLD1	XM_017005703.1 link	c.386A>G	p.Asn129Ser	missense_variant	Exon 5 of 12		XP_016861192.1	Q8TCW7-1
ZPLD1	XM_017005704.1 link	c.386A>G	p.Asn129Ser	missense_variant	Exon 4 of 11		XP_016861193.1	Q8TCW7-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ZPLD1	ENST00000466937.2 link	c.386A>G	p.Asn129Ser	missense_variant	Exon 5 of 12	1	NM_001329788.2	ENSP00000418253.1	Q8TCW7-1
ZPLD1	ENST00000306176.5 link	c.434A>G	p.Asn145Ser	missense_variant	Exon 4 of 11	1		ENSP00000307801.1	Q8TCW7-2
ZPLD1	ENST00000491959.5 link	c.386A>G	p.Asn129Ser	missense_variant	Exon 11 of 18	1		ENSP00000420265.1	Q8TCW7-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000319

AC:

AN:

251086

Hom.:

AF XY:

0.0000295

AC XY:

AN XY:

135674

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000232

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000103

AC:

AN:

1461432

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

727000

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000246

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:

0.00000270

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152204

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74360

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000343

Hom.:

Bravo

AF:

0.0000340

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Sep 03, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.434A>G (p.N145S) alteration is located in exon 4 (coding exon 4) of the ZPLD1 gene. This alteration results from a A to G substitution at nucleotide position 434, causing the asparagine (N) at amino acid position 145 to be replaced by a serine (S). 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

0.091

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.31

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.36

T;.;T

Eigen

Pathogenic

0.68

Eigen_PC

Pathogenic

0.68

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.92

.;D;D

M_CAP

Benign

0.076

MetaRNN

Uncertain

0.53

D;D;D

MetaSVM

Uncertain

0.35

MutationAssessor

Uncertain

2.0

M;.;M

PrimateAI

Uncertain

0.65

PROVEAN

Benign

-2.3

N;N;N

REVEL

Uncertain

0.50

Sift

Benign

0.30

T;T;T

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

0.98

D;D;D

Vest4

0.47

MutPred

0.47

Gain of glycosylation at N129 (P = 0.0118);.;Gain of glycosylation at N129 (P = 0.0118);

MVP

0.83

MPC

0.24

ClinPred

0.77

GERP RS

5.5

Varity_R

0.20

gMVP

0.57

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over