3-102456283-C-T

Position:

• chr3-102456283-C-T

Variant summary

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

The NM_001329788.2(ZPLD1):​c.418C>T​(p.Pro140Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,461,610 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: ZPLD1 NM_001329788.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.55

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 2 ACMG points.

• 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.418C>T	p.Pro140Ser	missense_variant	5/12	ENST00000466937.2	NP_001316717.1
ZPLD1	NM_175056.2	c.466C>T	p.Pro156Ser	missense_variant	4/11		NP_778226.1
ZPLD1	XM_017005703.1	c.418C>T	p.Pro140Ser	missense_variant	5/12		XP_016861192.1
ZPLD1	XM_017005704.1	c.418C>T	p.Pro140Ser	missense_variant	4/11		XP_016861193.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZPLD1	ENST00000466937.2	c.418C>T	p.Pro140Ser	missense_variant	5/12	1	NM_001329788.2	ENSP00000418253.1
ZPLD1	ENST00000306176.5	c.466C>T	p.Pro156Ser	missense_variant	4/11	1		ENSP00000307801.1
ZPLD1	ENST00000491959.5	c.418C>T	p.Pro140Ser	missense_variant	11/18	1		ENSP00000420265.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1461610 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727114

Gnomad4 AFR exome AF: 0.000120

Gnomad4 AMR exome AF: 0.00

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: 0.00

Gnomad4 OTH exome AF: 0.0000331

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

Jun 24, 2022

The c.466C>T (p.P156S) alteration is located in exon 4 (coding exon 4) of the ZPLD1 gene. This alteration results from a C to T substitution at nucleotide position 466, causing the proline (P) at amino acid position 156 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	0.12
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.059	T;.;T
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.86	.;D;D
M_CAP	Benign	0.063	D
MetaRNN	Uncertain	0.49	T;T;T
MetaSVM	Uncertain	-0.25	T
MutationAssessor	Benign	1.1	L;.;L
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	-0.45	N;N;N
REVEL	Uncertain	0.45
Sift	Benign	0.43	T;T;T
Sift4G	Uncertain	0.049	D;D;D
Polyphen		0.32	B;D;B
Vest4		0.66
MutPred		0.27		Loss of catalytic residue at P139 (P = 0.083);.;Loss of catalytic residue at P139 (P = 0.083);
MVP		0.81
MPC		0.096
ClinPred		0.83	D
GERP RS		5.5
Varity_R		0.14
gMVP		0.56

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: rs1707411543; hg19: chr3-102175127;