3-102477020-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001329788.2(ZPLD1):c.1051C>G(p.Pro351Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,461,372 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: ZPLD1 NM_001329788.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.77

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3685561).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZPLD1	NM_001329788.2	c.1051C>G	p.Pro351Ala	missense_variant	11/12	ENST00000466937.2
ZPLD1	NM_175056.2	c.1099C>G	p.Pro367Ala	missense_variant	10/11
ZPLD1	XM_017005703.1	c.1051C>G	p.Pro351Ala	missense_variant	11/12
ZPLD1	XM_017005704.1	c.1051C>G	p.Pro351Ala	missense_variant	10/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZPLD1	ENST00000466937.2	c.1051C>G	p.Pro351Ala	missense_variant	11/12	1	NM_001329788.2	P1
ZPLD1	ENST00000306176.5	c.1099C>G	p.Pro367Ala	missense_variant	10/11	1
ZPLD1	ENST00000491959.5	c.1051C>G	p.Pro351Ala	missense_variant	17/18	1		P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000796 AC: 2 AN: 251174 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135744

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000654

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461372 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727004

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: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

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

Oct 25, 2023

The c.1099C>G (p.P367A) alteration is located in exon 10 (coding exon 10) of the ZPLD1 gene. This alteration results from a C to G substitution at nucleotide position 1099, causing the proline (P) at amino acid position 367 to be replaced by an alanine (A). 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	0.065
BayesDel_addAF	Benign	-0.072	T
BayesDel_noAF	Benign	-0.16
Cadd	Uncertain	23
Dann	Uncertain	0.98
DEOGEN2	Benign	0.0076	T;.;T
Eigen	Uncertain	0.26
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Uncertain	0.97	D
M_CAP	Benign	0.050	D
MetaRNN	Benign	0.37	T;T;T
MetaSVM	Benign	-0.41	T
MutationAssessor	Uncertain	2.0	M;.;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-1.4	N;N;N
REVEL	Uncertain	0.39
Sift	Benign	0.16	T;T;T
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		0.82	P;P;P
Vest4		0.57
MutPred		0.13		Loss of glycosylation at P351 (P = 0.0238);.;Loss of glycosylation at P351 (P = 0.0238);
MVP		0.84
MPC		0.12
ClinPred		0.46	T
GERP RS		4.8
Varity_R		0.15
gMVP		0.62

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: rs749708892; hg19: chr3-102195864;