dbSNP rs1431206502: NPIPA1:p.Ile101Thr (chr16-14945846-T-C) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

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

The NM_006985.4(NPIPA1):c.302T>C(p.Ile101Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00025 ( 0 hom., cov: 9)

Exomes 𝑓: 0.000032 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

NPIPA1
NM_006985.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.196

Variant links:

Genes affected

NPIPA1 (HGNC:7909): (nuclear pore complex interacting protein family member A1) Predicted to be involved in mRNA transport and protein transport. Located in nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

NPIPA1 links:

PKD1P3-NPIPA1 (HGNC:):

PKD1P3-NPIPA1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.022180468).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPIPA1	NM_006985.4 link	c.302T>C	p.Ile101Thr	missense_variant	Exon 4 of 8	ENST00000328085.10	NP_008916.2	Q9UND3
PKD1P3-NPIPA1	NR_146231.1 link	n.6509T>C		non_coding_transcript_exon_variant	Exon 34 of 39

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NPIPA1	ENST00000328085.10 link	c.302T>C	p.Ile101Thr	missense_variant	Exon 4 of 8	1	NM_006985.4	ENSP00000331843.6		Q9UND3

Frequencies

GnomAD3 genomes

AF:

0.000245

AC:

AN:

65196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00115

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000189

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:

0.000263

AC:

AN:

11416

AF XY:

0.000313

show subpopulations

Gnomad AFR exome

AF:

0.00510

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000316

AC:

AN:

442614

Hom.:

Cov.:

AF XY:

0.0000173

AC XY:

AN XY:

231856

show subpopulations

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

African (AFR)

AF:

0.000818

AC:

AN:

12222

American (AMR)

AF:

0.000161

AC:

AN:

18660

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

13684

East Asian (EAS)

AF:

0.00

AC:

AN:

30560

South Asian (SAS)

AF:

0.00

AC:

AN:

44966

European-Finnish (FIN)

AF:

0.00

AC:

AN:

29856

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1934

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

264970

Other (OTH)

AF:

0.0000388

AC:

AN:

25762

⚠️ 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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.257

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000245

AC:

AN:

65242

Hom.:

Cov.:

AF XY:

0.000308

AC XY:

AN XY:

29228

show subpopulations

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

African (AFR)

AF:

0.00114

AC:

AN:

13156

American (AMR)

AF:

0.000189

AC:

AN:

5280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2020

East Asian (EAS)

AF:

0.00

AC:

AN:

1304

South Asian (SAS)

AF:

0.00

AC:

AN:

1412

European-Finnish (FIN)

AF:

0.00

AC:

AN:

4672

Middle Eastern (MID)

AF:

0.00

AC:

AN:

176

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

35968

Other (OTH)

AF:

0.00

AC:

AN:

726

⚠️ 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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.300

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000843

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 14, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.302T>C (p.I101T) alteration is located in exon 4 (coding exon 4) of the NPIPA1 gene. This alteration results from a T to C substitution at nucleotide position 302, causing the isoleucine (I) at amino acid position 101 to be replaced by a threonine (T). 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

Uncertain

0.38

BayesDel_addAF

Benign

-0.072

BayesDel_noAF

Benign

-0.34

CADD

Benign

8.1

(source)

DANN

Benign

0.82

DEOGEN2

Benign

0.13

T;.

Eigen

Benign

-0.50

Eigen_PC

Benign

-0.83

FATHMM_MKL

Benign

0.00087

LIST_S2

Benign

0.80

T;T

M_CAP

Benign

0.0062

MetaRNN

Benign

0.022

T;T

MetaSVM

Benign

-0.86

MutationAssessor

Uncertain

2.2

M;.

PROVEAN

Uncertain

-2.8

D;D

REVEL

Benign

0.15

Sift

Uncertain

0.0010

D;D

Sift4G

Pathogenic

0.0010

D;D

Polyphen

0.91

P;.

Vest4

0.14

MutPred

0.67

Gain of helix (P = 0.0022);.;

MVP

0.16

MPC

3.0

ClinPred

0.14

GERP RS

0.11

PromoterAI

0.00010

Neutral

(source)

Varity_R

0.39

gMVP

0.0014

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

Below is the list of publications found by LitVar. It may be empty.

rs1431206502

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over