chr7-76611535-C-G

Variant names:

• chr7-76611535-C-G
• rs371703975
• NM_012230.5:c.494G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_012230.5(POMZP3):​c.494G>C​(p.Cys165Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000349 in 1,605,162 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000027 (0 hom., cov: 28)
  • Exomes 𝑓: 0.000036 (0 hom.)
• Consequence: POMZP3 NM_012230.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.50
• Publications: 0 publications found

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]

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 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
POMZP3	NM_012230.5	c.494G>C	p.Cys165Ser	missense_variant	Exon 6 of 7	ENST00000310842.9	NP_036362.3
POMZP3	NM_152992.4	c.346-1320G>C		intron_variant	Intron 4 of 4		NP_694537.1
LINC03009	NR_029411.1	n.625-14386C>G		intron_variant	Intron 2 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POMZP3	ENST00000310842.9	c.494G>C	p.Cys165Ser	missense_variant	Exon 6 of 7	1	NM_012230.5	ENSP00000309233.4

Frequencies

GnomAD3 genomes AF: 0.0000266 AC: 4 AN: 150586 Hom.: 0 Cov.: 28

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: 0.0000445

Gnomad OTH AF: 0.000487

GnomAD2 exomes AF: 0.0000240 AC: 6 AN: 249830 AF XY: 0.0000222

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000533

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000357 AC: 52 AN: 1454576 Hom.: 0 Cov.: 61 AF XY: 0.0000263 AC XY: 19 AN XY: 723746

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33444

American (AMR) AF: 0.00 AC: 0 AN: 44642

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26102

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86152

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53304

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5744

European-Non Finnish (NFE) AF: 0.0000461 AC: 51 AN: 1105342

Other (OTH) AF: 0.0000166 AC: 1 AN: 60152

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000266 AC: 4 AN: 150586 Hom.: 0 Cov.: 28 AF XY: 0.0000272 AC XY: 2 AN XY: 73492

African (AFR) AF: 0.00 AC: 0 AN: 40942

American (AMR) AF: 0.00 AC: 0 AN: 15032

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4790

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10514

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000445 AC: 3 AN: 67396

Other (OTH) AF: 0.000487 AC: 1 AN: 2052

Alfa AF: 0.00 Hom.: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000495 AC: 6

EpiCase AF: 0.00

EpiControl AF: 0.0000596

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 24, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.494G>C (p.C165S) alteration is located in exon 6 (coding exon 5) of the POMZP3 gene. This alteration results from a G to C substitution at nucleotide position 494, causing the cysteine (C) at amino acid position 165 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	Pathogenic	0.72
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.15	T
Eigen	Benign	0.16
Eigen_PC	Benign	-0.10
FATHMM_MKL	Benign	0.086	N
LIST_S2	Benign	0.69	T
M_CAP	Benign	0.0018	T
MetaRNN	Uncertain	0.62	D
MetaSVM	Benign	-0.87	T
MutationAssessor	Pathogenic	3.0	M
PhyloP100		2.5
PROVEAN	Pathogenic	-6.8	D
REVEL	Benign	0.17
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.060	T
Polyphen		1.0	D
Vest4		0.51
MutPred		0.54		Gain of relative solvent accessibility (P = 0.005);
MVP		0.11
MPC		0.062
ClinPred		0.94	D
GERP RS		0.79
Varity_R		0.53
gMVP		0.82
Mutation Taster		=94/6	polymorphism

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

Other links and lift over

dbSNP: rs371703975; hg19: chr7-76240852;