6-17616599-G-A

Position:

• chr6-17616599-G-A

Variant summary

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

The NM_005124.4(NUP153):​c.4271C>T​(p.Pro1424Leu) variant causes a missense change. 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: 5.61

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=0.27370924).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NUP153	NM_005124.4	c.4271C>T	p.Pro1424Leu	missense_variant	21/22	ENST00000262077.3	NP_005115.2
NUP153	NM_001278209.2	c.4364C>T	p.Pro1455Leu	missense_variant	22/23		NP_001265138.1
NUP153	NM_001278210.2	c.4145C>T	p.Pro1382Leu	missense_variant	20/21		NP_001265139.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NUP153	ENST00000262077.3	c.4271C>T	p.Pro1424Leu	missense_variant	21/22	1	NM_005124.4	ENSP00000262077.3
NUP153	ENST00000613258.4	c.4145C>T	p.Pro1382Leu	missense_variant	20/21	1		ENSP00000478627.1
NUP153	ENST00000537253.5	c.4364C>T	p.Pro1455Leu	missense_variant	22/23	2		ENSP00000444029.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 07, 2023

The c.4271C>T (p.P1424L) alteration is located in exon 21 (coding exon 21) of the NUP153 gene. This alteration results from a C to T substitution at nucleotide position 4271, causing the proline (P) at amino acid position 1424 to be replaced by a leucine (L). 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	0.16
BayesDel_addAF	Uncertain	0.053	T
BayesDel_noAF	Benign	-0.16
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.094	.;.;T
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D;D;D
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.27	T;T;T
MetaSVM	Benign	-0.71	T
MutationAssessor	Uncertain	2.3	.;.;M
PrimateAI	Benign	0.47	T
PROVEAN	Pathogenic	-5.0	.;D;D
REVEL	Benign	0.15
Sift	Uncertain	0.0010	.;D;D
Sift4G	Uncertain	0.0030	D;D;D
Polyphen		0.99	.;.;D
Vest4		0.25
MutPred		0.21		.;.;Loss of glycosylation at T1423 (P = 0.0486);
MVP		0.35
MPC		0.036
ClinPred		0.99	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.39
gMVP		0.54

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-17616830;