6-17625981-G-A

Position:

• chr6-17625981-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_005124.4(NUP153):​c.3728C>T​(p.Thr1243Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000616 in 1,461,880 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: NUP153 NM_005124.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.93

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 Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.06338325).
• BS2: High AC in GnomAdExome4 at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NUP153	NM_005124.4	c.3728C>T	p.Thr1243Ile	missense_variant	19/22	ENST00000262077.3	NP_005115.2
NUP153	NM_001278209.2	c.3821C>T	p.Thr1274Ile	missense_variant	20/23		NP_001265138.1
NUP153	NM_001278210.2	c.3602C>T	p.Thr1201Ile	missense_variant	18/21		NP_001265139.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NUP153	ENST00000262077.3	c.3728C>T	p.Thr1243Ile	missense_variant	19/22	1	NM_005124.4	ENSP00000262077.3
NUP153	ENST00000613258.4	c.3602C>T	p.Thr1201Ile	missense_variant	18/21	1		ENSP00000478627.1
NUP153	ENST00000537253.5	c.3821C>T	p.Thr1274Ile	missense_variant	20/23	2		ENSP00000444029.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461880 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 727242

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000809

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000113

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

Apr 09, 2024

The c.3728C>T (p.T1243I) alteration is located in exon 19 (coding exon 19) of the NUP153 gene. This alteration results from a C to T substitution at nucleotide position 3728, causing the threonine (T) at amino acid position 1243 to be replaced by an isoleucine (I). 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	Benign	-0.31	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.017	.;.;T
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.32
FATHMM_MKL	Benign	0.68	D
LIST_S2	Benign	0.85	T;T;T
M_CAP	Benign	0.0063	T
MetaRNN	Benign	0.063	T;T;T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	0.0	.;.;N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-2.0	.;N;N
REVEL	Benign	0.077
Sift	Uncertain	0.017	.;D;T
Sift4G	Benign	0.28	T;T;T
Polyphen		0.0030	.;.;B
Vest4		0.14
MutPred		0.18		.;.;Loss of glycosylation at T1243 (P = 0.0588);
MVP		0.18
MPC		0.038
ClinPred		0.25	T
GERP RS		4.7
Varity_R		0.074
gMVP		0.26

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1280938259; hg19: chr6-17626212;