Genetic Variant NIPAL3:p.Pro127Pro (chr1-24445231-G-A) – ACMG Classification: Benign (-11 pts)

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_StrongBP6_ModerateBP7BS2

The NM_020448.5(NIPAL3):c.381G>A(p.Pro127Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00456 in 1,608,812 control chromosomes in the GnomAD database, including 31 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0040 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0046 ( 30 hom. )

Consequence

NIPAL3
NM_020448.5 synonymous

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.173

Publications

3 publications found

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -11 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.63).

BP6

Variant 1-24445231-G-A is Benign according to our data. Variant chr1-24445231-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 2638495.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

Synonymous conserved (PhyloP=-0.173 with no splicing effect.

BS2

High Homozygotes in GnomAdExome4 at 30 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NIPAL3	NM_020448.5 link	c.381G>A	p.Pro127Pro	synonymous_variant	Exon 5 of 12	ENST00000374399.9	NP_065181.1	Q6P499-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
NIPAL3	ENST00000374399.9 link	c.381G>A	p.Pro127Pro	synonymous_variant	Exon 5 of 12	1	NM_020448.5	ENSP00000363520.4	Q6P499-1
NIPAL3	ENST00000003912.9 link	c.135G>A	p.Pro45Pro	synonymous_variant	Exon 6 of 13	1		ENSP00000003912.3	Q6P499-2
NIPAL3	ENST00000358028.8 link	c.381G>A	p.Pro127Pro	synonymous_variant	Exon 5 of 8	1		ENSP00000350722.4	Q6P499-3
NIPAL3	ENST00000339255.2 link	c.381G>A	p.Pro127Pro	synonymous_variant	Exon 5 of 12	5		ENSP00000343549.2	A6NN97

Frequencies

GnomAD3 genomes

AF:

0.00398

AC:

606

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000796

Gnomad AMI

AF:

0.0231

Gnomad AMR

AF:

0.00622

Gnomad ASJ

AF:

0.00403

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.00245

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00570

Gnomad OTH

AF:

0.0105

GnomAD2 exomes

AF:

0.00415

AC:

1043

AN:

251120

AF XY:

0.00445

show subpopulations

Gnomad AFR exome

AF:

0.000923

Gnomad AMR exome

AF:

0.00383

Gnomad ASJ exome

AF:

0.00427

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00370

Gnomad NFE exome

AF:

0.00624

Gnomad OTH exome

AF:

0.00686

GnomAD4 exome

AF:

0.00462

AC:

6726

AN:

1456510

Hom.:

Cov.:

AF XY:

0.00468

AC XY:

3393

AN XY:

724944

show subpopulations

African (AFR)

AF:

0.00111

AC:

AN:

33388

American (AMR)

AF:

0.00385

AC:

172

AN:

44670

Ashkenazi Jewish (ASJ)

AF:

0.00391

AC:

102

AN:

26108

East Asian (EAS)

AF:

0.00

AC:

AN:

39672

South Asian (SAS)

AF:

0.000952

AC:

AN:

86104

European-Finnish (FIN)

AF:

0.00384

AC:

205

AN:

53396

Middle Eastern (MID)

AF:

0.0120

AC:

AN:

5748

European-Non Finnish (NFE)

AF:

0.00521

AC:

5769

AN:

1107196

Other (OTH)

AF:

0.00482

AC:

290

AN:

60228

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.454

Heterozygous variant carriers

272

544

816

1088

1360

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

210

420

630

840

1050

<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:

0.00398

AC:

606

AN:

152302

Hom.:

Cov.:

AF XY:

0.00381

AC XY:

284

AN XY:

74474

show subpopulations

African (AFR)

AF:

0.000794

AC:

AN:

41574

American (AMR)

AF:

0.00621

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00403

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5178

South Asian (SAS)

AF:

0.00104

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00245

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00570

AC:

388

AN:

68018

Other (OTH)

AF:

0.0104

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

119

149

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00378

Hom.:

Bravo

AF:

0.00458

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.00786

EpiControl

AF:

0.00628

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Nov 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

NIPAL3: BP4, BP7, BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.63

CADD

Benign

(source)

DANN

Benign

0.61

PhyloP100

-0.17

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over