6-17616174-C-A

Position:

• chr6-17616174-C-A

Variant summary

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

The NM_005124.4(NUP153):​c.4351G>T​(p.Gly1451Trp) variant causes a missense change. The variant allele was found at a frequency of 0.000315 in 1,576,472 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00027 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00032 (1 hom.)
• Consequence: NUP153 NM_005124.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.07

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=0.052980393).
• BS2: High AC in GnomAd4 at 39 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NUP153	NM_005124.4	c.4351G>T	p.Gly1451Trp	missense_variant	22/22	ENST00000262077.3	NP_005115.2
NUP153	NM_001278209.2	c.4444G>T	p.Gly1482Trp	missense_variant	23/23		NP_001265138.1
NUP153	NM_001278210.2	c.4225G>T	p.Gly1409Trp	missense_variant	21/21		NP_001265139.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NUP153	ENST00000262077.3	c.4351G>T	p.Gly1451Trp	missense_variant	22/22	1	NM_005124.4	ENSP00000262077.3
NUP153	ENST00000613258.4	c.4225G>T	p.Gly1409Trp	missense_variant	21/21	1		ENSP00000478627.1
NUP153	ENST00000537253.5	c.4444G>T	p.Gly1482Trp	missense_variant	23/23	2		ENSP00000444029.1

Frequencies

GnomAD3 genomes AF: 0.000268 AC: 39 AN: 145668 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00117

Gnomad ASJ AF: 0.000875

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000108

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000268

Gnomad OTH AF: 0.000502

GnomAD3 exomes AF: 0.000303 AC: 76 AN: 251140 Hom.: 1 AF XY: 0.000273 AC XY: 37 AN XY: 135744

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000290

Gnomad ASJ exome AF: 0.00278

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.000326

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000319 AC: 457 AN: 1430694 Hom.: 1 Cov.: 30 AF XY: 0.000302 AC XY: 215 AN XY: 711272

Gnomad4 AFR exome AF: 0.0000305

Gnomad4 AMR exome AF: 0.000229

Gnomad4 ASJ exome AF: 0.00292

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000196

Gnomad4 NFE exome AF: 0.000322

Gnomad4 OTH exome AF: 0.000360

GnomAD4 genome AF: 0.000268 AC: 39 AN: 145778 Hom.: 0 Cov.: 31 AF XY: 0.000355 AC XY: 25 AN XY: 70370

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00117

Gnomad4 ASJ AF: 0.000875

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000108

Gnomad4 NFE AF: 0.000268

Gnomad4 OTH AF: 0.000497

Alfa AF: 0.000392 Hom.: 0

Bravo AF: 0.000257

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000239 AC: 29

EpiCase AF: 0.000600

EpiControl AF: 0.000356

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 07, 2022

The c.4351G>T (p.G1451W) alteration is located in exon 22 (coding exon 22) of the NUP153 gene. This alteration results from a G to T substitution at nucleotide position 4351, causing the glycine (G) at amino acid position 1451 to be replaced by a tryptophan (W). 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	Pathogenic	0.61
BayesDel_addAF	Benign	-0.064	T
BayesDel_noAF	Uncertain	-0.020
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Benign	0.085	.;.;T
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D;D;D
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.053	T;T;T
MetaSVM	Benign	-0.65	T
MutationAssessor	Uncertain	2.4	.;.;M
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-3.8	.;D;D
REVEL	Benign	0.28
Sift	Pathogenic	0.0	.;D;D
Sift4G	Uncertain	0.0030	D;D;D
Polyphen		1.0	.;.;D
Vest4		0.58
MVP		0.49
MPC		0.26
ClinPred		0.69	D
GERP RS		4.8
Varity_R		0.59
gMVP		0.61

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: rs144981009; hg19: chr6-17616405;