rs777285421

Variant names:

• chr5-37291911-G-A
• rs777285421
• NM_153485.3:c.4165C>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_153485.3(NUP155):​c.4165C>T​(p.Arg1389Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000328 in 1,613,692 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000029 (0 hom.)
• Consequence: NUP155 NM_153485.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.84

Genes affected

NUP155 (HGNC:8063): (nucleoporin 155) Nucleoporins are proteins that play an important role in the assembly and functioning of the nuclear pore complex (NPC) which regulates the movement of macromolecules across the nuclear envelope (NE). The protein encoded by this gene plays a role in the fusion of NE vesicles and formation of the double membrane NE. The protein may also be involved in cardiac physiology and may be associated with the pathogenesis of atrial fibrillation. Alternative splicing results in multiple transcript variants of this gene. A pseudogene associated with this gene is located on chromosome 6. [provided by RefSeq, May 2013]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22982761).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NUP155	NM_153485.3	c.4165C>T	p.Arg1389Trp	missense_variant	Exon 35 of 35	ENST00000231498.8	NP_705618.1
NUP155	NM_004298.4	c.3988C>T	p.Arg1330Trp	missense_variant	Exon 35 of 35		NP_004289.1
NUP155	NM_001278312.2	c.3973C>T	p.Arg1325Trp	missense_variant	Exon 34 of 34		NP_001265241.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NUP155	ENST00000231498.8	c.4165C>T	p.Arg1389Trp	missense_variant	Exon 35 of 35	1	NM_153485.3	ENSP00000231498.3

Frequencies

GnomAD3 genomes AF: 0.0000657 AC: 10 AN: 152106 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000517 AC: 13 AN: 251410 Hom.: 0 AF XY: 0.0000662 AC XY: 9 AN XY: 135894

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.000816

GnomAD4 exome AF: 0.0000294 AC: 43 AN: 1461586 Hom.: 0 Cov.: 30 AF XY: 0.0000344 AC XY: 25 AN XY: 727100

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000128

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000144

Gnomad4 OTH exome AF: 0.0000828

GnomAD4 genome AF: 0.0000657 AC: 10 AN: 152106 Hom.: 0 Cov.: 33 AF XY: 0.0000673 AC XY: 5 AN XY: 74298

Gnomad4 AFR AF: 0.0000724

Gnomad4 AMR AF: 0.000197

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000327 Hom.: 0

Bravo AF: 0.000110

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.0000577 AC: 7

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 08, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.4165C>T (p.R1389W) alteration is located in exon 35 (coding exon 35) of the NUP155 gene. This alteration results from a C to T substitution at nucleotide position 4165, causing the arginine (R) at amino acid position 1389 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	Uncertain	0.49
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Pathogenic	0.25
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.63	D;.;T
Eigen	Benign	0.19
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.94	D;D;D
M_CAP	Benign	0.050	D
MetaRNN	Benign	0.23	T;T;T
MetaSVM	Uncertain	-0.19	T
MutationAssessor	Benign	2.0	M;.;.
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-5.8	D;D;D
REVEL	Uncertain	0.63
Sift	Uncertain	0.0010	D;D;D
Sift4G	Uncertain	0.0030	D;D;D
Polyphen		0.58	P;.;P
Vest4		0.22
MutPred		0.42		Gain of catalytic residue at L1387 (P = 0.0028);.;.;
MVP		0.92
MPC		0.17
ClinPred		0.40	T
GERP RS		4.2
Varity_R		0.54
gMVP		0.41

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: rs777285421; hg19: chr5-37292013; COSMIC: COSV51533045; COSMIC: COSV51533045;