7-76626043-G-C

Position:

• chr7-76626043-G-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_012230.5(POMZP3):​c.22C>G​(p.Leu8Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00433 in 1,598,800 control chromosomes in the GnomAD database, including 157 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.011 (17 hom., cov: 32)
  • Exomes 𝑓: 0.0037 (140 hom.)
• Consequence: POMZP3 NM_012230.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.30

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

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003779769).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0107 (1624/152208) while in subpopulation NFE AF= 0.0158 (1075/68006). AF 95% confidence interval is 0.015. There are 17 homozygotes in gnomad4. There are 758 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 17 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POMZP3	NM_012230.5	c.22C>G	p.Leu8Val	missense_variant	2/7	ENST00000310842.9	NP_036362.3
LINC03009	NR_029411.1	n.747G>C		non_coding_transcript_exon_variant	3/3
POMZP3	NM_152992.4	c.22C>G	p.Leu8Val	missense_variant	2/5		NP_694537.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POMZP3	ENST00000310842.9	c.22C>G	p.Leu8Val	missense_variant	2/7	1	NM_012230.5	ENSP00000309233	P1
LINC03009	ENST00000418663.5	n.728G>C		non_coding_transcript_exon_variant	3/3	1

Frequencies

GnomAD3 genomes AF: 0.0107 AC: 1623 AN: 152090 Hom.: 17 Cov.: 32

Gnomad AFR AF: 0.00797

Gnomad AMI AF: 0.0121

Gnomad AMR AF: 0.00694

Gnomad ASJ AF: 0.00663

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.00386

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0158

Gnomad OTH AF: 0.0115

GnomAD3 exomes AF: 0.00161 AC: 405 AN: 250904 Hom.: 6 AF XY: 0.00142 AC XY: 193 AN XY: 135624

Gnomad AFR exome AF: 0.00265

Gnomad AMR exome AF: 0.00119

Gnomad ASJ exome AF: 0.00119

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.000261

Gnomad FIN exome AF: 0.000278

Gnomad NFE exome AF: 0.00247

Gnomad OTH exome AF: 0.00212

GnomAD4 exome AF: 0.00367 AC: 5305 AN: 1446592 Hom.: 140 Cov.: 32 AF XY: 0.00362 AC XY: 2606 AN XY: 719984

Gnomad4 AFR exome AF: 0.00312

Gnomad4 AMR exome AF: 0.00208

Gnomad4 ASJ exome AF: 0.00349

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.000951

Gnomad4 FIN exome AF: 0.00326

Gnomad4 NFE exome AF: 0.00407

Gnomad4 OTH exome AF: 0.00484

GnomAD4 genome AF: 0.0107 AC: 1624 AN: 152208 Hom.: 17 Cov.: 32 AF XY: 0.0102 AC XY: 758 AN XY: 74426

Gnomad4 AFR AF: 0.00797

Gnomad4 AMR AF: 0.00693

Gnomad4 ASJ AF: 0.00663

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.00228

Gnomad4 FIN AF: 0.00386

Gnomad4 NFE AF: 0.0158

Gnomad4 OTH AF: 0.0114

Alfa AF: 0.0124 Hom.: 1

Bravo AF: 0.0108

ExAC AF: 0.0000330 AC: 4

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

Nov 17, 2022

The c.22C>G (p.L8V) alteration is located in exon 2 (coding exon 1) of the POMZP3 gene. This alteration results from a C to G substitution at nucleotide position 22, causing the leucine (L) at amino acid position 8 to be replaced by a valine (V). 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	0.045
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	15
DANN	Benign	0.88
DEOGEN2	Benign	0.0016	.;T;.
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.0037	N
LIST_S2	Benign	0.060	T;T;T
M_CAP	Benign	0.0016	T
MetaRNN	Benign	0.0038	T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-3.0	N;N;.
MutationTaster	Benign	1.0	N;N;N;N
PROVEAN	Benign	1.7	N;N;N
REVEL	Benign	0.033
Sift	Benign	1.0	T;T;T
Sift4G	Benign	1.0	T;T;.
Polyphen		0.0020	.;B;.
Vest4		0.22
MVP		0.082
MPC		1.6
ClinPred		0.0049	T
GERP RS		0.69
Varity_R		0.032
gMVP		0.070

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: rs200164764; hg19: chr7-76255360; COSMIC: COSV51886171; COSMIC: COSV51886171;