NM_001310137.5:c.1808C>T

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001310137.5(NPIPB11):​c.1808C>T​(p.Pro603Leu) 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 0.0016 (0 hom., cov: 22)
  • Exomes 𝑓: 0.00010 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NPIPB11 NM_001310137.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.123
• Publications: 3 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 -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.018564612).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPIPB11	NM_001310137.5	c.1808C>T	p.Pro603Leu	missense_variant	Exon 8 of 8	ENST00000698511.1	NP_001297066.2
NPIPB11	XM_047434576.1	c.1808C>T	p.Pro603Leu	missense_variant	Exon 7 of 8		XP_047290532.1
NPIPB11	XM_047434577.1	c.1442C>T	p.Pro481Leu	missense_variant	Exon 8 of 9		XP_047290533.1
NPIPB11	XM_047434578.1	c.1385C>T	p.Pro462Leu	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>T	p.Pro603Leu	missense_variant	Exon 8 of 8		NM_001310137.5	ENSP00000513761.1
NPIPB11	ENST00000524087.5	c.1808C>T	p.Pro603Leu	missense_variant	Exon 8 of 8	5		ENSP00000430853.1
RRN3P2	ENST00000769491.1	n.899+18065G>A		intron_variant	Intron 5 of 5

Frequencies

GnomAD3 genomes AF: 0.00162 AC: 219 AN: 135588 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.00155

Gnomad AMI AF: 0.00258

Gnomad AMR AF: 0.00116

Gnomad ASJ AF: 0.00217

Gnomad EAS AF: 0.000446

Gnomad SAS AF: 0.00170

Gnomad FIN AF: 0.00434

Gnomad MID AF: 0.00446

Gnomad NFE AF: 0.00140

Gnomad OTH AF: 0.00106

GnomAD2 exomes AF: 0.0000982 AC: 24 AN: 244338 AF XY: 0.000105

Gnomad AFR exome AF: 0.0000694

Gnomad AMR exome AF: 0.0000293

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000473

Gnomad NFE exome AF: 0.0000726

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000105 AC: 150 AN: 1431258 Hom.: 0 Cov.: 33 AF XY: 0.0000982 AC XY: 70 AN XY: 712592

African (AFR) AF: 0.000124 AC: 4 AN: 32194

American (AMR) AF: 0.0000463 AC: 2 AN: 43150

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25728

East Asian (EAS) AF: 0.0000514 AC: 2 AN: 38924

South Asian (SAS) AF: 0.0000587 AC: 5 AN: 85132

European-Finnish (FIN) AF: 0.000550 AC: 29 AN: 52698

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4082

European-Non Finnish (NFE) AF: 0.0000825 AC: 90 AN: 1090542

Other (OTH) AF: 0.000306 AC: 18 AN: 58808

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00162 AC: 220 AN: 135682 Hom.: 0 Cov.: 22 AF XY: 0.00181 AC XY: 120 AN XY: 66392

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

African (AFR) AF: 0.00158 AC: 57 AN: 36124

American (AMR) AF: 0.00116 AC: 16 AN: 13844

Ashkenazi Jewish (ASJ) AF: 0.00217 AC: 7 AN: 3228

East Asian (EAS) AF: 0.000447 AC: 2 AN: 4476

South Asian (SAS) AF: 0.00194 AC: 8 AN: 4122

European-Finnish (FIN) AF: 0.00434 AC: 39 AN: 8988

Middle Eastern (MID) AF: 0.00476 AC: 1 AN: 210

European-Non Finnish (NFE) AF: 0.00140 AC: 87 AN: 62022

Other (OTH) AF: 0.000529 AC: 1 AN: 1892

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00311 Hom.: 0

ExAC AF: 0.000498 AC: 60

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.59
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	17
DANN	Benign	0.94
DEOGEN2	Benign	0.012	T
Eigen	Benign	-0.93
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.0024	N
LIST_S2	Benign	0.55	T
M_CAP	Benign	0.0015	T
MetaRNN	Benign	0.019	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N
PhyloP100		0.12
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.013
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0020	D
Vest4		0.12
MutPred		0.33		Loss of disorder (P = 0.0174);
MVP		0.40
ClinPred		0.016	T
Varity_R		0.051
gMVP		0.0072
Mutation Taster		=100/0	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: rs536085707; hg19: chr16-29394445; COSMIC: COSV67324747; COSMIC: COSV67324747;