12-68690646-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_020401.4(NUP107):c.203G>A(p.Arg68Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000018 in 1,614,114 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000059 (1 hom., cov: 31)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: NUP107 NM_020401.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 6.32

Genes affected

NUP107 (HGNC:29914): (nucleoporin 107) This gene encodes a member of the nucleoporin family. The protein is localized to the nuclear rim and is an essential component of the nuclear pore complex (NPC). All molecules entering or leaving the nucleus either diffuse through or are actively transported by the NPC. Alternate transcriptional splice variants of this gene have been observed but have not been thoroughly characterized. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM1: In a modified_residue Omega-N-methylarginine (size 0) in uniprot entity NU107_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.28852445).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NUP107	NM_020401.4	c.203G>A	p.Arg68Gln	missense_variant	4/28	ENST00000229179.9
NUP107	NM_001330192.2	c.116G>A	p.Arg39Gln	missense_variant	4/28
NUP107	XM_005269037.5	c.203G>A	p.Arg68Gln	missense_variant	4/27

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NUP107	ENST00000229179.9	c.203G>A	p.Arg68Gln	missense_variant	4/28	1	NM_020401.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000592 AC: 9 AN: 152146 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251302 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135794

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000137 AC: 20 AN: 1461850 Hom.: 0 Cov.: 30 AF XY: 0.0000151 AC XY: 11 AN XY: 727234

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000126

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000591 AC: 9 AN: 152264 Hom.: 1 Cov.: 31 AF XY: 0.0000806 AC XY: 6 AN XY: 74442

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.0000900 Hom.: 0

Bravo AF: 0.0000227

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 09, 2023

The c.203G>A (p.R68Q) alteration is located in exon 4 (coding exon 4) of the NUP107 gene. This alteration results from a G to A substitution at nucleotide position 203, causing the arginine (R) at amino acid position 68 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Mar 04, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Not Available"). This variant has not been reported in the literature in individuals affected with NUP107-related conditions. This variant is present in population databases (rs551358105, gnomAD 0.006%). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 68 of the NUP107 protein (p.Arg68Gln). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Uncertain	0.018	T
BayesDel_noAF	Uncertain	-0.040
Cadd	Uncertain	24
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.083	T;.
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.29	T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Uncertain	2.1	M;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.85	N;N
REVEL	Benign	0.18
Sift	Benign	0.086	T;T
Sift4G	Benign	0.19	T;T
Polyphen		0.99	D;.
Vest4		0.57
MutPred		0.16		Loss of glycosylation at S67 (P = 0.0934);.;
MVP		0.62
MPC		0.64
ClinPred		0.57	D
GERP RS		5.6
Varity_R		0.087
gMVP		0.44

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs551358105; hg19: chr12-69084426;