chr1-24449609-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_020448.5(NIPAL3):​c.523C>T​(p.Pro175Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000342 in 1,461,280 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

NIPAL3
NM_020448.5 missense

Scores

5
9
5

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.02
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.806

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
NIPAL3NM_020448.5 linkc.523C>T p.Pro175Ser missense_variant Exon 6 of 12 ENST00000374399.9 NP_065181.1 Q6P499-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
NIPAL3ENST00000374399.9 linkc.523C>T p.Pro175Ser missense_variant Exon 6 of 12 1 NM_020448.5 ENSP00000363520.4 Q6P499-1
NIPAL3ENST00000003912.7 linkc.277C>T p.Pro93Ser missense_variant Exon 7 of 13 1 ENSP00000003912.3 Q6P499-2
NIPAL3ENST00000358028.8 linkc.523C>T p.Pro175Ser missense_variant Exon 6 of 8 1 ENSP00000350722.4 Q6P499-3
NIPAL3ENST00000339255.2 linkc.523C>T p.Pro175Ser missense_variant Exon 6 of 12 5 ENSP00000343549.2 A6NN97

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000342
AC:
5
AN:
1461280
Hom.:
0
Cov.:
31
AF XY:
0.00000413
AC XY:
3
AN XY:
726898
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.0000383
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000360
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Feb 14, 2023
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.523C>T (p.P175S) alteration is located in exon 6 (coding exon 5) of the NIPAL3 gene. This alteration results from a C to T substitution at nucleotide position 523, causing the proline (P) at amino acid position 175 to be replaced by a serine (S). 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
0.24
BayesDel_addAF
Pathogenic
0.23
D
BayesDel_noAF
Uncertain
0.090
CADD
Pathogenic
27
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.64
D;.;.;.
Eigen
Uncertain
0.66
Eigen_PC
Pathogenic
0.73
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.88
D;D;D;D
M_CAP
Benign
0.052
D
MetaRNN
Pathogenic
0.81
D;D;D;D
MetaSVM
Uncertain
0.39
D
MutationAssessor
Benign
1.7
L;.;L;.
PrimateAI
Uncertain
0.65
T
PROVEAN
Benign
-2.3
N;N;N;N
REVEL
Uncertain
0.58
Sift
Uncertain
0.028
D;D;T;D
Sift4G
Uncertain
0.022
D;D;D;D
Polyphen
0.79
P;.;D;P
Vest4
0.76
MutPred
0.53
Gain of catalytic residue at P175 (P = 0.1899);.;Gain of catalytic residue at P175 (P = 0.1899);Gain of catalytic residue at P175 (P = 0.1899);
MVP
0.92
MPC
0.69
ClinPred
0.89
D
GERP RS
6.2
Varity_R
0.46
gMVP
0.82

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-24776099; API