Genetic Variant NIPSNAP3B:p.Pro19Leu (chr9-104764296-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_018376.4(NIPSNAP3B):c.56C>T(p.Pro19Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000034 in 1,585,990 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000033 ( 0 hom. )

Consequence

NIPSNAP3B
NM_018376.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.747

Publications

0 publications found

Variant links:

Genes affected

NIPSNAP3B (HGNC:23641): (nipsnap homolog 3B) NIPSNAP3B belongs to a family of proteins with putative roles in vesicular trafficking (Buechler et al., 2004 [PubMed 15177564]).[supplied by OMIM, Mar 2008]

NIPSNAP3B links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.19260725).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NIPSNAP3B	NM_018376.4 link	c.56C>T	p.Pro19Leu	missense_variant	Exon 1 of 6	ENST00000374762.4	NP_060846.2	Q9BS92Q71RE8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
NIPSNAP3B	ENST00000374762.4 link	c.56C>T	p.Pro19Leu	missense_variant	Exon 1 of 6	1	NM_018376.4	ENSP00000363894.3	Q9BS92
NIPSNAP3B	ENST00000460936.5 link	n.56C>T		non_coding_transcript_exon_variant	Exon 1 of 6	5		ENSP00000435209.1	F2Z3L7
NIPSNAP3B	ENST00000461177.1 link	n.102C>T		non_coding_transcript_exon_variant	Exon 1 of 6	3

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152232

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.0000735

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.0000456

AC:

AN:

197578

AF XY:

0.0000558

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.0000814

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000328

AC:

AN:

1433758

Hom.:

Cov.:

AF XY:

0.0000380

AC XY:

AN XY:

710722

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32940

American (AMR)

AF:

0.0000248

AC:

AN:

40374

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25574

East Asian (EAS)

AF:

0.00

AC:

AN:

38450

South Asian (SAS)

AF:

0.000146

AC:

AN:

81994

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50454

Middle Eastern (MID)

AF:

0.000241

AC:

AN:

4152

European-Non Finnish (NFE)

AF:

0.0000245

AC:

AN:

1100598

Other (OTH)

AF:

0.000101

AC:

AN:

59222

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152232

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74380

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41468

American (AMR)

AF:

0.0000654

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10632

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000735

AC:

AN:

68038

Other (OTH)

AF:

0.000478

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000614

Hom.:

Bravo

AF:

0.0000378

ExAC

AF:

0.0000587

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 18, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.56C>T (p.P19L) alteration is located in exon 1 (coding exon 1) of the NIPSNAP3B gene. This alteration results from a C to T substitution at nucleotide position 56, causing the proline (P) at amino acid position 19 to be replaced by a leucine (L). 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

Benign

0.12

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.18

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.026

Eigen

Benign

-0.40

Eigen_PC

Benign

-0.37

FATHMM_MKL

Benign

0.67

LIST_S2

Benign

0.71

M_CAP

Benign

0.036

MetaRNN

Benign

0.19

MetaSVM

Benign

-0.89

MutationAssessor

Uncertain

2.2

PhyloP100

0.75

PrimateAI

Uncertain

0.59

PROVEAN

Benign

-2.0

REVEL

Benign

0.18

Sift

Benign

0.10

Sift4G

Benign

0.32

Polyphen

0.0070

Vest4

0.29

MutPred

0.48

Loss of loop (P = 0.0128);

MVP

0.65

MPC

0.031

ClinPred

0.13

GERP RS

2.7

PromoterAI

0.054

Neutral

(source)

Varity_R

0.062

gMVP

0.31

Mutation Taster

=86/14

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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9-104764296-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over