Genetic Variant POMZP3:p.Ser139Cys (chr7-76611743-G-C) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_012230.5(POMZP3):c.416C>G(p.Ser139Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00012 in 1,534,684 control chromosomes in the GnomAD database, including 16 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000065 ( 0 hom., cov: 22)

Exomes 𝑓: 0.00013 ( 16 hom. )

Consequence

POMZP3
NM_012230.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.55

Publications

1 publications found

Variant links:

Genes affected

POMZP3 (HGNC:9203): (POM121 and ZP3 fusion) This gene appears to have resulted from a fusion of DNA sequences derived from 2 distinct loci, specifically through the duplication of two internal exons from the POM121 gene and four 3' exons from the ZP3 gene. The 5' end of this gene is similar to the 5` coding region of the POM121 gene which encodes an integral nuclear pore membrane protein. However, the protein encoded by this gene lacks the nuclear pore localization motif. The 3' end of this gene is similar to the last 4 exons of the zona pellucida glycoprotein 3 (ZP3) gene and the encoded protein retains one zona pellucida domain. Multiple protein isoforms are encoded by transcript variants of this gene. [provided by RefSeq, Jul 2008]

POMZP3 links:

LINC03009 (HGNC:56134): (long intergenic non-protein coding RNA 3009)

LINC03009 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BS2

High Homozygotes in GnomAdExome4 at 16 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POMZP3	NM_012230.5 link	c.416C>G	p.Ser139Cys	missense_variant	Exon 5 of 7	ENST00000310842.9	NP_036362.3	Q6PJE2-4
POMZP3	NM_152992.4 link	c.346-1528C>G		intron_variant	Intron 4 of 4		NP_694537.1	Q6PJE2-5
LINC03009	NR_029411.1 link	n.625-14178G>C		intron_variant	Intron 2 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POMZP3	ENST00000310842.9 link	c.416C>G	p.Ser139Cys	missense_variant	Exon 5 of 7	1	NM_012230.5	ENSP00000309233.4		Q6PJE2-4

Frequencies

GnomAD3 genomes

AF:

0.0000649

AC:

AN:

138702

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000714

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000990

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000111

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000468

AC:

AN:

235080

AF XY:

0.0000395

show subpopulations

Gnomad AFR exome

AF:

0.0000674

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000870

Gnomad OTH exome

AF:

0.000175

GnomAD4 exome

AF:

0.000125

AC:

175

AN:

1395982

Hom.:

Cov.:

AF XY:

0.000109

AC XY:

AN XY:

694958

show subpopulations

African (AFR)

AF:

0.0000623

AC:

AN:

32122

American (AMR)

AF:

0.00

AC:

AN:

43996

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24742

East Asian (EAS)

AF:

0.00

AC:

AN:

39668

South Asian (SAS)

AF:

0.00

AC:

AN:

84162

European-Finnish (FIN)

AF:

0.0000189

AC:

AN:

52810

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5080

European-Non Finnish (NFE)

AF:

0.000157

AC:

166

AN:

1055450

Other (OTH)

AF:

0.000104

AC:

AN:

57952

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.545

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000649

AC:

AN:

138702

Hom.:

Cov.:

AF XY:

0.0000296

AC XY:

AN XY:

67542

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

35816

American (AMR)

AF:

0.0000714

AC:

AN:

14000

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3146

East Asian (EAS)

AF:

0.00

AC:

AN:

5118

South Asian (SAS)

AF:

0.00

AC:

AN:

4358

European-Finnish (FIN)

AF:

0.0000990

AC:

AN:

10106

Middle Eastern (MID)

AF:

0.00

AC:

AN:

282

European-Non Finnish (NFE)

AF:

0.000111

AC:

AN:

63238

Other (OTH)

AF:

0.00

AC:

AN:

1800

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.542

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000285

Hom.:

Bravo

AF:

0.0000718

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000118

AC:

ExAC

AF:

0.0000335

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 04, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.416C>G (p.S139C) alteration is located in exon 5 (coding exon 4) of the POMZP3 gene. This alteration results from a C to G substitution at nucleotide position 416, causing the serine (S) at amino acid position 139 to be replaced by a cysteine (C). 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

Uncertain

0.44

BayesDel_addAF

Uncertain

0.019

BayesDel_noAF

Uncertain

-0.020

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.77

D;.

Eigen

Uncertain

0.26

Eigen_PC

Benign

-0.0038

FATHMM_MKL

Benign

0.30

LIST_S2

Uncertain

0.93

D;D

M_CAP

Benign

0.0072

MetaRNN

Uncertain

0.65

D;D

MetaSVM

Uncertain

0.43

MutationAssessor

Pathogenic

3.4

M;.

PhyloP100

3.5

PROVEAN

Uncertain

-3.8

D;D

REVEL

Uncertain

0.60

Sift

Pathogenic

0.0

D;D

Sift4G

Uncertain

0.0050

D;.

Polyphen

1.0

D;.

Vest4

0.50

MVP

0.42

MPC

0.064

ClinPred

0.65

GERP RS

0.79

Varity_R

0.63

gMVP

0.52

Mutation Taster

=78/22

polymorphism

(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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chr7-76611743-G-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over