chr1-24449609-C-T

Variant names:

• chr1-24449609-C-T
• NM_020448.5:c.523C>T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.02

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]

ACMG classification

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
NIPAL3	NM_020448.5	c.523C>T	p.Pro175Ser	missense_variant	Exon 6 of 12	ENST00000374399.9	NP_065181.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NIPAL3	ENST00000374399.9	c.523C>T	p.Pro175Ser	missense_variant	Exon 6 of 12	1	NM_020448.5	ENSP00000363520.4
NIPAL3	ENST00000003912.7	c.277C>T	p.Pro93Ser	missense_variant	Exon 7 of 13	1		ENSP00000003912.3
NIPAL3	ENST00000358028.8	c.523C>T	p.Pro175Ser	missense_variant	Exon 6 of 8	1		ENSP00000350722.4
NIPAL3	ENST00000339255.2	c.523C>T	p.Pro175Ser	missense_variant	Exon 6 of 12	5		ENSP00000343549.2

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

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

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;