chr7-76618196-T-G

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_012230.5(POMZP3):​c.332A>C​(p.Asp111Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict 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. D111V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 24)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: POMZP3 NM_012230.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.24
• 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.16030034).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POMZP3	NM_012230.5	c.332A>C	p.Asp111Ala	missense_variant	Exon 4 of 7	ENST00000310842.9	NP_036362.3
POMZP3	NM_152992.4	c.332A>C	p.Asp111Ala	missense_variant	Exon 4 of 5		NP_694537.1
LINC03009	NR_029411.1	n.625-7725T>G		intron_variant	Intron 2 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POMZP3	ENST00000310842.9	c.332A>C	p.Asp111Ala	missense_variant	Exon 4 of 7	1	NM_012230.5	ENSP00000309233.4

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 150524 Hom.: 0 Cov.: 24

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000832 AC: 2 AN: 240306 AF XY: 0.00000765

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000295

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000940

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 6.85e-7 AC: 1 AN: 1459090 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 725864

⚠️ 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: 33436

American (AMR) AF: 0.00 AC: 0 AN: 44696

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39680

South Asian (SAS) AF: 0.00 AC: 0 AN: 86202

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53376

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 9.01e-7 AC: 1 AN: 1109550

Other (OTH) AF: 0.00 AC: 0 AN: 60294

⚠️ 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 Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 150524 Hom.: 0 Cov.: 24 AF XY: 0.00 AC XY: 0 AN XY: 73444

African (AFR) AF: 0.00 AC: 0 AN: 40770

American (AMR) AF: 0.00 AC: 0 AN: 15016

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3460

East Asian (EAS) AF: 0.00 AC: 0 AN: 5102

South Asian (SAS) AF: 0.00 AC: 0 AN: 4744

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10450

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67716

Other (OTH) AF: 0.00 AC: 0 AN: 2044

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000165 AC: 2

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	22
DANN	Benign	0.96
DEOGEN2	Uncertain	0.50	.;D;.
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.47
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.73	T;D;D
M_CAP	Benign	0.0034	T
MetaRNN	Benign	0.16	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	2.0	M;M;.
PhyloP100		2.2
PROVEAN	Benign	-2.0	N;D;D
REVEL	Benign	0.089
Sift	Uncertain	0.0080	D;T;D
Sift4G	Uncertain	0.025	D;T;.
Polyphen		0.97	.;D;.
Vest4		0.39
MutPred		0.58		Loss of sheet (P = 0.0457);Loss of sheet (P = 0.0457);.;
MVP		0.13
MPC		3.1
ClinPred		0.21	T
PromoterAI		0.0096	Neutral
Varity_R		0.12
gMVP		0.40
Mutation Taster		=90/10	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: rs774512789; hg19: chr7-76247513;