Genetic Variant ZPLD1:p.Thr50Met (chr3-102452961-C-T) – ACMG Classification: Likely_benign (-1 pts)

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_001329788.2(ZPLD1):c.149C>T(p.Thr50Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000096 in 1,614,032 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T50R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000099 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000096 ( 1 hom. )

Consequence

ZPLD1
NM_001329788.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.48

Publications

1 publications found

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 was made for transcript

Our verdict: Likely_benign. The variant received -1 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.26608014).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001329788.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZPLD1	NM_001329788.2	MANE Select	c.149C>T	p.Thr50Met	missense	Exon 4 of 12	NP_001316717.1	Q8TCW7-1
	ZPLD1	NM_175056.2		c.197C>T	p.Thr66Met	missense	Exon 3 of 11	NP_778226.1	Q8TCW7-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ZPLD1	ENST00000466937.2	TSL:1 MANE Select	c.149C>T	p.Thr50Met	missense	Exon 4 of 12	ENSP00000418253.1	Q8TCW7-1
ZPLD1	ENST00000306176.5	TSL:1	c.197C>T	p.Thr66Met	missense	Exon 3 of 11	ENSP00000307801.1	Q8TCW7-2
ZPLD1	ENST00000491959.5	TSL:1	c.149C>T	p.Thr50Met	missense	Exon 10 of 18	ENSP00000420265.1	Q8TCW7-1

Frequencies

GnomAD3 genomes

AF:

0.0000986

AC:

AN:

152096

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00125

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000215

AC:

AN:

251398

AF XY:

0.000228

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.000202

Gnomad ASJ exome

AF:

0.00

Gnomad EAS 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:

0.0000958

AC:

140

AN:

1461818

Hom.:

Cov.:

AF XY:

0.000120

AC XY:

AN XY:

727210

show subpopulations

African (AFR)

AF:

0.0000896

AC:

AN:

33472

American (AMR)

AF:

0.000179

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.00133

AC:

115

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000450

AC:

AN:

1111952

Other (OTH)

AF:

0.000116

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000985

AC:

AN:

152214

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

74406

show subpopulations

African (AFR)

AF:

0.000169

AC:

AN:

41536

American (AMR)

AF:

0.0000654

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00125

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10588

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68010

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.538

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000656

Hom.:

Bravo

AF:

0.0000680

ExAC

AF:

0.000272

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.10

BayesDel_noAF

Uncertain

0.040

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.39

Eigen

Pathogenic

0.74

Eigen_PC

Pathogenic

0.73

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.97

M_CAP

Benign

0.052

MetaRNN

Benign

0.27

MetaSVM

Uncertain

0.29

MutationAssessor

Uncertain

2.4

PhyloP100

7.5

PrimateAI

Pathogenic

0.79

PROVEAN

Benign

-2.1

REVEL

Uncertain

0.54

Sift

Uncertain

0.024

Sift4G

Uncertain

0.0030

Polyphen

1.0

Vest4

0.82

MVP

0.86

MPC

0.38

ClinPred

0.13

GERP RS

6.0

Varity_R

0.20

gMVP

0.74

Mutation Taster

=46/54

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over