chr1-229487591-T-C

Variant names:

• chr1-229487591-T-C
• rs1065674
• NM_018230.3:c.1217A>G

Variant summary

Our verdict is Benign. The variant received -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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). 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
• Publications: 44 publications found

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]

NUP133 Gene-Disease associations (from GenCC):

• Galloway-Mowat syndrome 8

  Inheritance: AR, Unknown Classification: STRONG, LIMITED Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• familial idiopathic steroid-resistant nephrotic syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Galloway-Mowat syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• nephrotic syndrome, type 18

  Inheritance: AR, Unknown Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018230.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NUP133	NM_018230.3	MANE Select	c.1217A>G	p.Gln406Arg	missense	Exon 10 of 26	NP_060700.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NUP133	ENST00000261396.6	TSL:1 MANE Select	c.1217A>G	p.Gln406Arg	missense	Exon 10 of 26	ENSP00000261396.3

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

GnomAD2 exomes AF: 0.231 AC: 57236 AN: 247280 AF XY: 0.225

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 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

African (AFR) AF: 0.550 AC: 18312 AN: 33316

American (AMR) AF: 0.258 AC: 11304 AN: 43826

Ashkenazi Jewish (ASJ) AF: 0.379 AC: 9890 AN: 26072

East Asian (EAS) AF: 0.154 AC: 6079 AN: 39566

South Asian (SAS) AF: 0.188 AC: 16046 AN: 85280

European-Finnish (FIN) AF: 0.130 AC: 6946 AN: 53382

Middle Eastern (MID) AF: 0.287 AC: 1654 AN: 5756

European-Non Finnish (NFE) AF: 0.207 AC: 229308 AN: 1109138

Other (OTH) AF: 0.242 AC: 14546 AN: 60180

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

African (AFR) AF: 0.538 AC: 22285 AN: 41396

American (AMR) AF: 0.290 AC: 4429 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.385 AC: 1334 AN: 3464

East Asian (EAS) AF: 0.156 AC: 809 AN: 5176

South Asian (SAS) AF: 0.171 AC: 826 AN: 4826

European-Finnish (FIN) AF: 0.127 AC: 1346 AN: 10600

Middle Eastern (MID) AF: 0.320 AC: 94 AN: 294

European-Non Finnish (NFE) AF: 0.206 AC: 14018 AN: 67996

Other (OTH) AF: 0.318 AC: 672 AN: 2112

Alfa AF: 0.236 Hom.: 11964

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

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		1.8
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
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1065674; hg19: chr1-229623338; COSMIC: COSV54568365;