chr9-128999620-A-G

Variant names:

• chr9-128999620-A-G
• rs2302811
• NM_015354.3:c.3662-4A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_015354.3(NUP188):​c.3662-4A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.375 in 1,611,356 control chromosomes in the GnomAD database, including 117,674 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.31 (8591 hom., cov: 31)
  • Exomes 𝑓: 0.38 (109083 hom.)
• Consequence: NUP188 NM_015354.3 splice_region, intron
• Scores: Splicing: ADA: 0.00005606
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.120
• Publications: 17 publications found

Genes affected

NUP188 (HGNC:17859): (nucleoporin 188) The nuclear pore complex (NPC) is found on the nuclear envelope and forms a gateway that regulates the flow of proteins and RNAs between the cytoplasm and nucleoplasm. The NPC is comprised of approximately 30 distinct proteins collectively known as nucleoporins. Nucleoporins are pore-complex-specific glycoproteins which often have cytoplasmically oriented O-linked N-acetylglucosamine residues and numerous repeats of the pentapeptide sequence XFXFG. However, the nucleoporin protein encoded by this gene does not contain the typical FG repeat sequences found in most vertebrate nucleoporins. This nucleoporin is thought to form part of the scaffold for the central channel of the nuclear pore. [provided by RefSeq, Jan 2013]

NUP188 Gene-Disease associations (from GenCC):

• sandestig-stefanova syndrome

  Inheritance: AR, Unknown Classification: STRONG, MODERATE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics

LOC101929314 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 9-128999620-A-G is Benign according to our data. Variant chr9-128999620-A-G is described in ClinVar as Benign. ClinVar VariationId is 403264.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.392 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NUP188	NM_015354.3	c.3662-4A>G		splice_region_variant, intron_variant	Intron 33 of 43	ENST00000372577.2	NP_056169.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NUP188	ENST00000372577.2	c.3662-4A>G		splice_region_variant, intron_variant	Intron 33 of 43	1	NM_015354.3	ENSP00000361658.2
NUP188	ENST00000477069.5	n.1630-4A>G		splice_region_variant, intron_variant	Intron 14 of 18	1
NUP188	ENST00000487952.1	n.20A>G		non_coding_transcript_exon_variant	Exon 1 of 2	2

Frequencies

GnomAD3 genomes AF: 0.311 AC: 47285 AN: 151808 Hom.: 8581 Cov.: 31

Gnomad AFR AF: 0.122

Gnomad AMI AF: 0.337

Gnomad AMR AF: 0.393

Gnomad ASJ AF: 0.353

Gnomad EAS AF: 0.216

Gnomad SAS AF: 0.333

Gnomad FIN AF: 0.405

Gnomad MID AF: 0.380

Gnomad NFE AF: 0.396

Gnomad OTH AF: 0.336

GnomAD2 exomes AF: 0.361 AC: 90411 AN: 250458 AF XY: 0.364

Gnomad AFR exome AF: 0.111

Gnomad AMR exome AF: 0.429

Gnomad ASJ exome AF: 0.347

Gnomad EAS exome AF: 0.201

Gnomad FIN exome AF: 0.395

Gnomad NFE exome AF: 0.400

Gnomad OTH exome AF: 0.376

GnomAD4 exome AF: 0.381 AC: 556662 AN: 1459430 Hom.: 109083 Cov.: 33 AF XY: 0.381 AC XY: 276595 AN XY: 726050

African (AFR) AF: 0.114 AC: 3810 AN: 33456

American (AMR) AF: 0.426 AC: 19038 AN: 44662

Ashkenazi Jewish (ASJ) AF: 0.342 AC: 8934 AN: 26096

East Asian (EAS) AF: 0.194 AC: 7700 AN: 39676

South Asian (SAS) AF: 0.344 AC: 29687 AN: 86216

European-Finnish (FIN) AF: 0.393 AC: 20956 AN: 53256

Middle Eastern (MID) AF: 0.399 AC: 2301 AN: 5762

European-Non Finnish (NFE) AF: 0.399 AC: 442607 AN: 1109998

Other (OTH) AF: 0.359 AC: 21629 AN: 60308

GnomAD4 genome AF: 0.311 AC: 47302 AN: 151926 Hom.: 8591 Cov.: 31 AF XY: 0.313 AC XY: 23273 AN XY: 74254

African (AFR) AF: 0.122 AC: 5045 AN: 41418

American (AMR) AF: 0.394 AC: 6014 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.353 AC: 1224 AN: 3470

East Asian (EAS) AF: 0.217 AC: 1119 AN: 5166

South Asian (SAS) AF: 0.334 AC: 1605 AN: 4810

European-Finnish (FIN) AF: 0.405 AC: 4273 AN: 10552

Middle Eastern (MID) AF: 0.371 AC: 109 AN: 294

European-Non Finnish (NFE) AF: 0.396 AC: 26901 AN: 67924

Other (OTH) AF: 0.335 AC: 707 AN: 2110

Alfa AF: 0.370 Hom.: 17218

Bravo AF: 0.303

Asia WGS AF: 0.252 AC: 880 AN: 3478

EpiCase AF: 0.396

EpiControl AF: 0.394

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

NUP188-related disorder Benign:1

Oct 17, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Sandestig-stefanova syndrome Benign:1

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	5.1
DANN	Benign	0.47
PhyloP100		-0.12
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=93/7	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000056
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.010		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: rs2302811; hg19: chr9-131761899; COSMIC: COSV65361759; COSMIC: COSV65361759;