16-29383124-G-T

Variant names:

• chr16-29383124-G-T
• rs536085707
• NM_001310137.5:c.1808C>A

Variant summary

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

The NM_001310137.5(NPIPB11):​c.1808C>A​(p.Pro603Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 14/19 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. P603R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 22)
  • Exomes 𝑓: 0.0000028 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NPIPB11 NM_001310137.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.123
• Publications: 0 publications found

Genes affected

NPIPB11 (HGNC:37453): (nuclear pore complex interacting protein family member B11) Predicted to act upstream of or within prevention of polyspermy. Located in nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

RRN3P2 (HGNC:37619): (RRN3 pseudogene 2) Predicted to enable RNA polymerase I core binding activity and RNA polymerase I general transcription initiation factor activity. Predicted to be involved in transcription initiation from RNA polymerase I promoter. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.072971314).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPIPB11	NM_001310137.5	c.1808C>A	p.Pro603Gln	missense_variant	Exon 8 of 8	ENST00000698511.1	NP_001297066.2
NPIPB11	XM_047434576.1	c.1808C>A	p.Pro603Gln	missense_variant	Exon 7 of 8		XP_047290532.1
NPIPB11	XM_047434577.1	c.1442C>A	p.Pro481Gln	missense_variant	Exon 8 of 9		XP_047290533.1
NPIPB11	XM_047434578.1	c.1385C>A	p.Pro462Gln	missense_variant	Exon 8 of 9		XP_047290534.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NPIPB11	ENST00000698511.1	c.1808C>A	p.Pro603Gln	missense_variant	Exon 8 of 8		NM_001310137.5	ENSP00000513761.1
NPIPB11	ENST00000524087.5	c.1808C>A	p.Pro603Gln	missense_variant	Exon 8 of 8	5		ENSP00000430853.1
RRN3P2	ENST00000769491.1	n.899+18065G>T		intron_variant	Intron 5 of 5

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 137234 Hom.: 0 Cov.: 22

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

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000279 AC: 4 AN: 1432018 Hom.: 0 Cov.: 33 AF XY: 0.00000140 AC XY: 1 AN XY: 712904

⚠️ 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: 32216

American (AMR) AF: 0.00 AC: 0 AN: 43188

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25764

East Asian (EAS) AF: 0.00 AC: 0 AN: 38934

South Asian (SAS) AF: 0.00 AC: 0 AN: 85142

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52724

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4086

European-Non Finnish (NFE) AF: 0.00000367 AC: 4 AN: 1091088

Other (OTH) AF: 0.00 AC: 0 AN: 58876

⚠️ 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;AS_VQSR AF: 0.00 AC: 0 AN: 137340 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 67116

African (AFR) AF: 0.00 AC: 0 AN: 36502

American (AMR) AF: 0.00 AC: 0 AN: 14000

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3258

East Asian (EAS) AF: 0.00 AC: 0 AN: 4504

South Asian (SAS) AF: 0.00 AC: 0 AN: 4156

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9180

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 222

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 62808

Other (OTH) AF: 0.00 AC: 0 AN: 1920

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.62
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	16
DANN	Benign	0.94
DEOGEN2	Benign	0.0090	T
Eigen	Benign	-0.94
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.0027	N
LIST_S2	Benign	0.42	T
M_CAP	Benign	0.0013	T
MetaRNN	Benign	0.073	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N
PhyloP100		0.12
PROVEAN	Benign	-0.74	N
REVEL	Benign	0.023
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.0020	D
Vest4		0.15
MutPred		0.18		Loss of phosphorylation at S606 (P = 0.1471);
MVP		0.095
ClinPred		0.056	T
Varity_R		0.056
gMVP		0.0094

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: rs536085707; hg19: chr16-29394445;