7-76618196-T-A

Variant names:

• chr7-76618196-T-A
• rs774512789
• NM_012230.5:c.332A>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_012230.5(POMZP3):​c.332A>T​(p.Asp111Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 0.000011 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: POMZP3 NM_012230.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.24

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.24401012).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POMZP3	NM_012230.5	c.332A>T	p.Asp111Val	missense_variant	Exon 4 of 7	ENST00000310842.9	NP_036362.3
POMZP3	NM_152992.4	c.332A>T	p.Asp111Val	missense_variant	Exon 4 of 5		NP_694537.1
LINC03009	NR_029411.1	n.625-7725T>A		intron_variant	Intron 2 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POMZP3	ENST00000310842.9	c.332A>T	p.Asp111Val	missense_variant	Exon 4 of 7	1	NM_012230.5	ENSP00000309233.4

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD3 exomes AF: 0.0000166 AC: 4 AN: 240306 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 130688

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000376

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000110 AC: 16 AN: 1459090 Hom.: 0 Cov.: 30 AF XY: 0.00000689 AC XY: 5 AN XY: 725864

Gnomad4 AFR exome AF: 0.00

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: 0.0000126

Gnomad4 OTH exome AF: 0.0000332

GnomAD4 genome Cov.: 24

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 20, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.332A>T (p.D111V) alteration is located in exon 4 (coding exon 3) of the POMZP3 gene. This alteration results from a A to T substitution at nucleotide position 332, causing the aspartic acid (D) at amino acid position 111 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	0.30
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	22
DANN	Benign	0.75
DEOGEN2	Uncertain	0.55	.;D;.
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.41
FATHMM_MKL	Benign	0.11	N
LIST_S2	Uncertain	0.86	D;D;D
M_CAP	Benign	0.0070	T
MetaRNN	Benign	0.24	T;T;T
MetaSVM	Benign	-0.41	T
MutationAssessor	Uncertain	2.7	M;M;.
PROVEAN	Uncertain	-3.5	D;D;D
REVEL	Benign	0.23
Sift	Uncertain	0.0020	D;D;D
Sift4G	Uncertain	0.0050	D;D;.
Polyphen		0.85	.;P;.
Vest4		0.50
MutPred		0.60		Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);.;
MVP		0.26
MPC		3.2
ClinPred		0.31	T
Varity_R		0.23
gMVP		0.46

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: rs774512789; hg19: chr7-76247513;