Genetic Variant NIPAL3:p.Ala7Thr (chr1-24419566-G-A) – ACMG Classification: Benign (-9 pts)

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_020448.5(NIPAL3):c.19G>A(p.Ala7Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00345 in 1,613,788 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

Frequency

Genomes: 𝑓 0.0025 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0035 ( 14 hom. )

Consequence

NIPAL3
NM_020448.5 missense

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: 0.395

Variant links:

Genes affected

NIPAL3 (HGNC:25233): (NIPA like domain containing 3) Predicted to enable magnesium ion transmembrane transporter activity. Predicted to be involved in magnesium ion transport. Predicted to be integral component of membrane. Predicted to be active in membrane. [provided by Alliance of Genome Resources, Apr 2022]

NIPAL3 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0029473603).

BP6

Variant 1-24419566-G-A is Benign according to our data. Variant chr1-24419566-G-A is described in ClinVar as [Benign]. Clinvar id is 3033822.Status of the report is no_assertion_criteria_provided, 0 stars.

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NIPAL3	NM_020448.5 link	c.19G>A	p.Ala7Thr	missense_variant	Exon 2 of 12	ENST00000374399.9	NP_065181.1	Q6P499-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NIPAL3	ENST00000374399.9 link	c.19G>A	p.Ala7Thr	missense_variant	Exon 2 of 12	1	NM_020448.5	ENSP00000363520.4		Q6P499-1

Frequencies

GnomAD3 genomes

AF:

0.00248

AC:

377

AN:

152234

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000989

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

Gnomad ASJ

AF:

0.00202

Gnomad EAS

AF:

0.0110

Gnomad SAS

AF:

0.00269

Gnomad FIN

AF:

0.000659

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00363

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00278

AC:

690

AN:

248008

Hom.:

AF XY:

0.00271

AC XY:

364

AN XY:

134374

show subpopulations

Gnomad AFR exome

AF:

0.000500

Gnomad AMR exome

AF:

0.000348

Gnomad ASJ exome

AF:

0.00109

Gnomad EAS exome

AF:

0.0103

Gnomad SAS exome

AF:

0.000853

Gnomad FIN exome

AF:

0.000466

Gnomad NFE exome

AF:

0.00381

Gnomad OTH exome

AF:

0.00165

GnomAD4 exome

AF:

0.00355

AC:

5186

AN:

1461436

Hom.:

Cov.:

AF XY:

0.00356

AC XY:

2591

AN XY:

727008

show subpopulations

Gnomad4 AFR exome

AF:

0.000418

Gnomad4 AMR exome

AF:

0.000447

Gnomad4 ASJ exome

AF:

0.00142

Gnomad4 EAS exome

AF:

0.0153

Gnomad4 SAS exome

AF:

0.00102

Gnomad4 FIN exome

AF:

0.000824

Gnomad4 NFE exome

AF:

0.00378

Gnomad4 OTH exome

AF:

0.00277

GnomAD4 genome

AF:

0.00247

AC:

376

AN:

152352

Hom.:

Cov.:

AF XY:

0.00231

AC XY:

172

AN XY:

74502

show subpopulations

Gnomad4 AFR

AF:

0.000986

Gnomad4 AMR

AF:

0.000327

Gnomad4 ASJ

AF:

0.00202

Gnomad4 EAS

AF:

0.0110

Gnomad4 SAS

AF:

0.00269

Gnomad4 FIN

AF:

0.000659

Gnomad4 NFE

AF:

0.00362

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00339

Hom.:

Bravo

AF:

0.00227

TwinsUK

AF:

0.00485

AC:

ALSPAC

AF:

0.00441

AC:

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00279

AC:

ExAC

AF:

0.00268

AC:

326

Asia WGS

AF:

0.00491

AC:

AN:

3478

EpiCase

AF:

0.00294

EpiControl

AF:

0.00380

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

NIPAL3-related disorder

Benign:1

Jun 12, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.25

CADD

Benign

7.9

DANN

Uncertain

0.98

DEOGEN2

Benign

0.14

T;.;.

Eigen

Benign

-0.70

Eigen_PC

Benign

-0.75

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.65

T;T;T

M_CAP

Benign

0.069

MetaRNN

Benign

0.0029

T;T;T

MetaSVM

Uncertain

-0.24

MutationAssessor

Benign

1.4

L;L;.

PrimateAI

Benign

0.39

PROVEAN

Benign

-0.40

N;N;N

REVEL

Benign

0.081

Sift

Benign

0.062

T;T;T

Sift4G

Benign

0.21

T;T;T

Polyphen

0.027

B;B;B

Vest4

0.27

MVP

0.52

MPC

0.21

ClinPred

0.0012

GERP RS

2.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.026

gMVP

0.64

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over