Genetic Variant NM_020448.5:c.95A>C (chr1-24440173-A-C) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_020448.5(NIPAL3):c.95A>C(p.Glu32Ala) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

NIPAL3
NM_020448.5 missense, splice_region

Scores

Splicing: ADA: 0.5154

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.43

Publications

0 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.746

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020448.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NIPAL3	NM_020448.5	MANE Select	c.95A>C	p.Glu32Ala	missense splice_region	Exon 3 of 12	NP_065181.1	Q6P499-1
NIPAL3	NM_001322854.2		c.95A>C	p.Glu32Ala	missense splice_region	Exon 3 of 12	NP_001309783.1	Q6P499-1
NIPAL3	NM_001322855.2		c.95A>C	p.Glu32Ala	missense splice_region	Exon 4 of 13	NP_001309784.1	Q6P499-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NIPAL3	ENST00000374399.9	TSL:1 MANE Select	c.95A>C	p.Glu32Ala	missense splice_region	Exon 3 of 12	ENSP00000363520.4	Q6P499-1
NIPAL3	ENST00000003912.9	TSL:1	c.-152A>C		splice_region	Exon 4 of 13	ENSP00000003912.3
NIPAL3	ENST00000358028.8	TSL:1	c.95A>C	p.Glu32Ala	missense splice_region	Exon 3 of 8	ENSP00000350722.4	Q6P499-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1433358

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

712420

African (AFR)

AF:

0.00

AC:

AN:

32464

American (AMR)

AF:

0.00

AC:

AN:

40344

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24772

East Asian (EAS)

AF:

0.00

AC:

AN:

38112

South Asian (SAS)

AF:

0.00

AC:

AN:

81906

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52526

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5648

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1098608

Other (OTH)

AF:

0.00

AC:

AN:

58978

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.38

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Uncertain

-0.060

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.17

Eigen

Uncertain

0.56

Eigen_PC

Uncertain

0.55

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

M_CAP

Uncertain

0.24

MetaRNN

Pathogenic

0.75

MetaSVM

Uncertain

0.54

MutationAssessor

Benign

1.8

PhyloP100

7.4

PrimateAI

Uncertain

0.65

PROVEAN

Benign

-0.90

REVEL

Pathogenic

0.69

Sift

Uncertain

0.028

Sift4G

Uncertain

0.025

Polyphen

0.99

Vest4

0.70

MutPred

0.66

Loss of stability (P = 0.0828)

MVP

0.84

MPC

0.82

ClinPred

0.87

GERP RS

5.0

Varity_R

0.24

gMVP

0.54

Mutation Taster

=211/89

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.52

dbscSNV1_RF

Benign

0.63

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over