NM_005124.4:c.4111C>T

Variant names:

• chr6-17624624-G-A
• rs200132365
• NM_005124.4:c.4111C>T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_005124.4(NUP153):​c.4111C>T​(p.Pro1371Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: NUP153 NM_005124.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.94

Genes affected

NUP153 (HGNC:8062): (nucleoporin 153) Nuclear pore complexes regulate the transport of macromolecules between the nucleus and cytoplasm. They are composed of at least 100 different polypeptide subunits, many of which belong to the nucleoporin family. Nucleoporins are glycoproteins found in nuclear pores and contain characteristic pentapeptide XFXFG repeats as well as O-linked N-acetylglucosamine residues oriented towards the cytoplasm. The protein encoded by this gene has three distinct domains: a N-terminal region containing a pore targeting and an RNA-binding domain domain, a central region containing multiple zinc finger motifs, and a C-terminal region containing multiple XFXFG repeats. Alternative splicing results in multiple transcript variants of this gene. [provided by RefSeq, May 2013]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27316457).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NUP153	NM_005124.4	c.4111C>T	p.Pro1371Ser	missense_variant	Exon 20 of 22	ENST00000262077.3	NP_005115.2
NUP153	NM_001278209.2	c.4204C>T	p.Pro1402Ser	missense_variant	Exon 21 of 23		NP_001265138.1
NUP153	NM_001278210.2	c.3985C>T	p.Pro1329Ser	missense_variant	Exon 19 of 21		NP_001265139.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NUP153	ENST00000262077.3	c.4111C>T	p.Pro1371Ser	missense_variant	Exon 20 of 22	1	NM_005124.4	ENSP00000262077.3
NUP153	ENST00000613258.4	c.3985C>T	p.Pro1329Ser	missense_variant	Exon 19 of 21	1		ENSP00000478627.1
NUP153	ENST00000537253.5	c.4204C>T	p.Pro1402Ser	missense_variant	Exon 21 of 23	2		ENSP00000444029.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 27, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.4111C>T (p.P1371S) alteration is located in exon 20 (coding exon 20) of the NUP153 gene. This alteration results from a C to T substitution at nucleotide position 4111, causing the proline (P) at amino acid position 1371 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	0.091
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.074	.;.;T
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.94	D;D;D
M_CAP	Benign	0.0076	T
MetaRNN	Benign	0.27	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.6	.;.;M
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-2.5	.;D;D
REVEL	Benign	0.069
Sift	Uncertain	0.013	.;D;D
Sift4G	Benign	0.13	T;T;T
Polyphen		0.96	.;.;D
Vest4		0.43
MutPred		0.23		.;.;Loss of catalytic residue at P1371 (P = 1e-04);
MVP		0.36
MPC		0.13
ClinPred		0.92	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.12
gMVP		0.38

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

Other links and lift over

dbSNP: rs200132365; hg19: chr6-17624855;