6-17632830-C-T

Variant names:

• chr6-17632830-C-T
• rs2274136
• NM_005124.4:c.2479G>A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005124.4(NUP153):​c.2479G>A​(p.Ala827Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.789 in 1,543,588 control chromosomes in the GnomAD database, including 479,008 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: 𝑓 0.77 (43738 hom., cov: 22)
  • Exomes 𝑓: 0.79 (435270 hom.)
• Consequence: NUP153 NM_005124.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.287

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.2234004E-6).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.866 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NUP153	NM_005124.4	c.2479G>A	p.Ala827Thr	missense_variant	Exon 17 of 22	ENST00000262077.3	NP_005115.2
NUP153	NM_001278209.2	c.2572G>A	p.Ala858Thr	missense_variant	Exon 18 of 23		NP_001265138.1
NUP153	NM_001278210.2	c.2353G>A	p.Ala785Thr	missense_variant	Exon 16 of 21		NP_001265139.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NUP153	ENST00000262077.3	c.2479G>A	p.Ala827Thr	missense_variant	Exon 17 of 22	1	NM_005124.4	ENSP00000262077.3
NUP153	ENST00000613258.4	c.2353G>A	p.Ala785Thr	missense_variant	Exon 16 of 21	1		ENSP00000478627.1
NUP153	ENST00000537253.5	c.2572G>A	p.Ala858Thr	missense_variant	Exon 18 of 23	2		ENSP00000444029.1

Frequencies

GnomAD3 genomes AF: 0.774 AC: 112814 AN: 145746 Hom.: 43706 Cov.: 22

Gnomad AFR AF: 0.730

Gnomad AMI AF: 0.877

Gnomad AMR AF: 0.787

Gnomad ASJ AF: 0.803

Gnomad EAS AF: 0.888

Gnomad SAS AF: 0.858

Gnomad FIN AF: 0.783

Gnomad MID AF: 0.858

Gnomad NFE AF: 0.778

Gnomad OTH AF: 0.785

GnomAD3 exomes AF: 0.795 AC: 168682 AN: 212070 Hom.: 67301 AF XY: 0.798 AC XY: 92425 AN XY: 115802

Gnomad AFR exome AF: 0.729

Gnomad AMR exome AF: 0.783

Gnomad ASJ exome AF: 0.805

Gnomad EAS exome AF: 0.884

Gnomad SAS exome AF: 0.863

Gnomad FIN exome AF: 0.778

Gnomad NFE exome AF: 0.781

Gnomad OTH exome AF: 0.790

GnomAD4 exome AF: 0.790 AC: 1104346 AN: 1397768 Hom.: 435270 Cov.: 26 AF XY: 0.792 AC XY: 551773 AN XY: 696262

Gnomad4 AFR exome AF: 0.736

Gnomad4 AMR exome AF: 0.783

Gnomad4 ASJ exome AF: 0.816

Gnomad4 EAS exome AF: 0.908

Gnomad4 SAS exome AF: 0.861

Gnomad4 FIN exome AF: 0.783

Gnomad4 NFE exome AF: 0.781

Gnomad4 OTH exome AF: 0.799

GnomAD4 genome AF: 0.774 AC: 112876 AN: 145820 Hom.: 43738 Cov.: 22 AF XY: 0.776 AC XY: 54760 AN XY: 70538

Gnomad4 AFR AF: 0.730

Gnomad4 AMR AF: 0.787

Gnomad4 ASJ AF: 0.803

Gnomad4 EAS AF: 0.888

Gnomad4 SAS AF: 0.858

Gnomad4 FIN AF: 0.783

Gnomad4 NFE AF: 0.778

Gnomad4 OTH AF: 0.786

Alfa AF: 0.784 Hom.: 86657

Bravo AF: 0.770

TwinsUK AF: 0.768 AC: 2849

ALSPAC AF: 0.768 AC: 2958

ESP6500AA AF: 0.727 AC: 3202

ESP6500EA AF: 0.771 AC: 6634

ExAC AF: 0.791 AC: 96018

Asia WGS AF: 0.872 AC: 3028 AN: 3472

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.81	T
BayesDel_noAF	Benign	-0.79
CADD	Benign	16
DANN	Benign	0.95
DEOGEN2	Benign	0.0034	.;.;T
Eigen	Benign	-0.75
Eigen_PC	Benign	-0.58
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.042	T;T;T
MetaRNN	Benign	0.0000012	T;T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.83	.;.;L
PrimateAI	Benign	0.24	T
PROVEAN	Benign	0.59	.;N;N
REVEL	Benign	0.031
Sift	Benign	0.72	.;T;T
Sift4G	Benign	0.27	T;T;T
Polyphen		0.0010	.;.;B
Vest4		0.049
MPC		0.032
ClinPred		0.0089	T
GERP RS		1.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.017
gMVP		0.22

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs2274136; hg19: chr6-17633061; COSMIC: COSV50468526;