1-229487591-T-C

Position:

• chr1-229487591-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_018230.3(NUP133):​c.1217A>G​(p.Gln406Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.224 in 1,608,564 control chromosomes in the GnomAD database, including 45,710 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q406W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.30 (8793 hom., cov: 32)
  • Exomes 𝑓: 0.22 (36917 hom.)
• Consequence: NUP133 NM_018230.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.80

Genes affected

NUP133 (HGNC:18016): (nucleoporin 133) The nuclear envelope creates distinct nuclear and cytoplasmic compartments in eukaryotic cells. It consists of two concentric membranes perforated by nuclear pores, large protein complexes that form aqueous channels to regulate the flow of macromolecules between the nucleus and the cytoplasm. These complexes are composed of at least 100 different polypeptide subunits, many of which belong to the nucleoporin family. The nucleoporin protein encoded by this gene displays evolutionarily conserved interactions with other nucleoporins. This protein, which localizes to both sides of the nuclear pore complex at interphase, remains associated with the complex during mitosis and is targeted at early stages to the reforming nuclear envelope. This protein also localizes to kinetochores of mitotic cells. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=2.0435452E-4).
• BP6: Variant 1-229487591-T-C is Benign according to our data. Variant chr1-229487591-T-C is described in ClinVar as [Benign]. Clinvar id is 1601070.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.532 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NUP133	NM_018230.3	c.1217A>G	p.Gln406Arg	missense_variant	10/26	ENST00000261396.6
NUP133	XM_047424979.1	c.1217A>G	p.Gln406Arg	missense_variant	10/19

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NUP133	ENST00000261396.6	c.1217A>G	p.Gln406Arg	missense_variant	10/26	1	NM_018230.3	P1

Frequencies

GnomAD3 genomes AF: 0.302 AC: 45942 AN: 151930 Hom.: 8761 Cov.: 32

Gnomad AFR AF: 0.538

Gnomad AMI AF: 0.229

Gnomad AMR AF: 0.289

Gnomad ASJ AF: 0.385

Gnomad EAS AF: 0.157

Gnomad SAS AF: 0.171

Gnomad FIN AF: 0.127

Gnomad MID AF: 0.323

Gnomad NFE AF: 0.206

Gnomad OTH AF: 0.319

GnomAD3 exomes AF: 0.231 AC: 57236 AN: 247280 Hom.: 7750 AF XY: 0.225 AC XY: 30055 AN XY: 133662

Gnomad AFR exome AF: 0.537

Gnomad AMR exome AF: 0.250

Gnomad ASJ exome AF: 0.386

Gnomad EAS exome AF: 0.170

Gnomad SAS exome AF: 0.191

Gnomad FIN exome AF: 0.131

Gnomad NFE exome AF: 0.208

Gnomad OTH exome AF: 0.237

GnomAD4 exome AF: 0.216 AC: 314085 AN: 1456516 Hom.: 36917 Cov.: 31 AF XY: 0.214 AC XY: 155150 AN XY: 724548

Gnomad4 AFR exome AF: 0.550

Gnomad4 AMR exome AF: 0.258

Gnomad4 ASJ exome AF: 0.379

Gnomad4 EAS exome AF: 0.154

Gnomad4 SAS exome AF: 0.188

Gnomad4 FIN exome AF: 0.130

Gnomad4 NFE exome AF: 0.207

Gnomad4 OTH exome AF: 0.242

GnomAD4 genome AF: 0.303 AC: 46021 AN: 152048 Hom.: 8793 Cov.: 32 AF XY: 0.296 AC XY: 22028 AN XY: 74330

Gnomad4 AFR AF: 0.538

Gnomad4 AMR AF: 0.290

Gnomad4 ASJ AF: 0.385

Gnomad4 EAS AF: 0.156

Gnomad4 SAS AF: 0.171

Gnomad4 FIN AF: 0.127

Gnomad4 NFE AF: 0.206

Gnomad4 OTH AF: 0.318

Alfa AF: 0.219 Hom.: 7389

Bravo AF: 0.328

TwinsUK AF: 0.205 AC: 759

ALSPAC AF: 0.207 AC: 798

ESP6500AA AF: 0.527 AC: 2321

ESP6500EA AF: 0.217 AC: 1863

ExAC AF: 0.233 AC: 28313

Asia WGS AF: 0.205 AC: 712 AN: 3478

EpiCase AF: 0.222

EpiControl AF: 0.224

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.052
BayesDel_addAF	Benign	-0.75	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	6.5
DANN	Benign	0.14
DEOGEN2	Benign	0.10	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.011	N
LIST_S2	Benign	0.26	T
MetaRNN	Benign	0.00020	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	-2.2	N
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.24	T
PROVEAN	Benign	1.1	N
REVEL	Benign	0.081
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.0040
MPC		0.16
ClinPred		0.00080	T
GERP RS		2.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.045
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: rs1065674; hg19: chr1-229623338; COSMIC: COSV54568365;