Genetic Variant NPIPB11:p.Ala553Ala (chr16-29383273-C-T) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBP7

The NM_001310137.5(NPIPB11):c.1659G>A(p.Ala553Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. A553A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000083 ( 0 hom., cov: 20)

Exomes 𝑓: 0.000054 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

NPIPB11
NM_001310137.5 synonymous

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.32

Publications

0 publications found

Variant links:

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]

NPIPB11 links:

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]

RRN3P2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.85).

BP7

Synonymous conserved (PhyloP=-1.32 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001310137.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPIPB11	NM_001310137.5	MANE Select	c.1659G>A	p.Ala553Ala	synonymous	Exon 8 of 8	NP_001297066.2	E5RHQ5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NPIPB11	ENST00000698511.1	MANE Select	c.1659G>A	p.Ala553Ala	synonymous	Exon 8 of 8	ENSP00000513761.1	E5RHQ5
NPIPB11	ENST00000524087.5	TSL:5	c.1659G>A	p.Ala553Ala	synonymous	Exon 8 of 8	ENSP00000430853.1	E5RHQ5
RRN3P2	ENST00000769491.1		n.899+18214C>T		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.00000832

AC:

AN:

120140

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000305

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:

0.0000359

AC:

AN:

222842

AF XY:

0.00000822

show subpopulations

Gnomad AFR exome

AF:

0.000145

Gnomad AMR exome

AF:

0.0000304

Gnomad ASJ exome

AF:

0.000115

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000304

Gnomad OTH exome

AF:

0.000183

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000540

AC:

AN:

1406542

Hom.:

Cov.:

AF XY:

0.0000601

AC XY:

AN XY:

698806

show subpopulations

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

African (AFR)

AF:

0.0000617

AC:

AN:

32394

American (AMR)

AF:

0.0000463

AC:

AN:

43238

Ashkenazi Jewish (ASJ)

AF:

0.0000411

AC:

AN:

24336

East Asian (EAS)

AF:

0.00

AC:

AN:

39314

South Asian (SAS)

AF:

0.0000608

AC:

AN:

82292

European-Finnish (FIN)

AF:

0.00

AC:

AN:

45672

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3874

European-Non Finnish (NFE)

AF:

0.0000585

AC:

AN:

1077838

Other (OTH)

AF:

0.0000521

AC:

AN:

57584

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.279

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000832

AC:

AN:

120140

Hom.:

Cov.:

AF XY:

0.0000171

AC XY:

AN XY:

58330

show subpopulations

African (AFR)

AF:

0.0000305

AC:

AN:

32748

American (AMR)

AF:

0.00

AC:

AN:

12120

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2768

East Asian (EAS)

AF:

0.00

AC:

AN:

4294

South Asian (SAS)

AF:

0.00

AC:

AN:

3838

European-Finnish (FIN)

AF:

0.00

AC:

AN:

7364

Middle Eastern (MID)

AF:

0.00

AC:

AN:

198

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

54508

Other (OTH)

AF:

0.00

AC:

AN:

1608

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000123

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

8.8

(source)

DANN

Benign

0.86

PhyloP100

-1.3

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over