6-17624770-T-C

Position:

• chr6-17624770-T-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_005124.4(NUP153):​c.3965A>G​(p.Asn1322Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,860 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 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: 6.8e-7 (0 hom.)
• Consequence: NUP153 NM_005124.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.324

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.042847365).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NUP153	NM_005124.4	c.3965A>G	p.Asn1322Ser	missense_variant	20/22	ENST00000262077.3	NP_005115.2
NUP153	NM_001278209.2	c.4058A>G	p.Asn1353Ser	missense_variant	21/23		NP_001265138.1
NUP153	NM_001278210.2	c.3839A>G	p.Asn1280Ser	missense_variant	19/21		NP_001265139.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NUP153	ENST00000262077.3	c.3965A>G	p.Asn1322Ser	missense_variant	20/22	1	NM_005124.4	ENSP00000262077.3
NUP153	ENST00000613258.4	c.3839A>G	p.Asn1280Ser	missense_variant	19/21	1		ENSP00000478627.1
NUP153	ENST00000537253.5	c.4058A>G	p.Asn1353Ser	missense_variant	21/23	2		ENSP00000444029.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461860 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727230

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: 8.99e-7

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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 13, 2023

The c.3965A>G (p.N1322S) alteration is located in exon 20 (coding exon 20) of the NUP153 gene. This alteration results from a A to G substitution at nucleotide position 3965, causing the asparagine (N) at amino acid position 1322 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	0.052
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.81
CADD	Benign	7.6
DANN	Benign	0.93
DEOGEN2	Benign	0.0062	.;.;T
Eigen	Benign	-0.95
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.51	D
LIST_S2	Uncertain	0.89	D;D;D
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.043	T;T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	-0.045	.;.;N
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.5	.;N;N
REVEL	Benign	0.055
Sift	Benign	0.40	.;T;T
Sift4G	Benign	1.0	T;T;T
Polyphen		0.0	.;.;B
Vest4		0.14
MutPred		0.13		.;.;Gain of glycosylation at N1322 (P = 0.0074);
MVP		0.27
MPC		0.028
ClinPred		0.064	T
GERP RS		-3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.026
gMVP		0.11

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: rs750780211; hg19: chr6-17625001;