rs2287363

Variant names:

• chr9-129005389-A-C
• rs2287363
• NM_015354.3:c.4596A>C

Your query was ambiguous. Multiple possible variants found:

• chr9-129005389-A-C
• chr9-129005389-A-G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_015354.3(NUP188):​c.4596A>C​(p.Ser1532Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.429 in 1,612,342 control chromosomes in the GnomAD database, including 149,330 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.44 (14717 hom., cov: 32)
  • Exomes 𝑓: 0.43 (134613 hom.)
• Consequence: NUP188 NM_015354.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.539
• Publications: 24 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant 9-129005389-A-C is Benign according to our data. Variant chr9-129005389-A-C is described in ClinVar as Benign. ClinVar VariationId is 403266.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.539 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.475 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NUP188	NM_015354.3	c.4596A>C	p.Ser1532Ser	synonymous_variant	Exon 40 of 44	ENST00000372577.2	NP_056169.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NUP188	ENST00000372577.2	c.4596A>C	p.Ser1532Ser	synonymous_variant	Exon 40 of 44	1	NM_015354.3	ENSP00000361658.2

Frequencies

GnomAD3 genomes AF: 0.438 AC: 66560 AN: 151884 Hom.: 14686 Cov.: 32

Gnomad AFR AF: 0.457

Gnomad AMI AF: 0.336

Gnomad AMR AF: 0.484

Gnomad ASJ AF: 0.397

Gnomad EAS AF: 0.391

Gnomad SAS AF: 0.396

Gnomad FIN AF: 0.451

Gnomad MID AF: 0.430

Gnomad NFE AF: 0.425

Gnomad OTH AF: 0.437

GnomAD2 exomes AF: 0.435 AC: 108657 AN: 249614 AF XY: 0.430

Gnomad AFR exome AF: 0.458

Gnomad AMR exome AF: 0.517

Gnomad ASJ exome AF: 0.393

Gnomad EAS exome AF: 0.387

Gnomad FIN exome AF: 0.441

Gnomad NFE exome AF: 0.427

Gnomad OTH exome AF: 0.430

GnomAD4 exome AF: 0.428 AC: 624941 AN: 1460342 Hom.: 134613 Cov.: 61 AF XY: 0.426 AC XY: 309655 AN XY: 726548

African (AFR) AF: 0.473 AC: 15832 AN: 33480

American (AMR) AF: 0.512 AC: 22894 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.387 AC: 10107 AN: 26134

East Asian (EAS) AF: 0.359 AC: 14248 AN: 39698

South Asian (SAS) AF: 0.399 AC: 34439 AN: 86250

European-Finnish (FIN) AF: 0.435 AC: 22596 AN: 51974

Middle Eastern (MID) AF: 0.449 AC: 2592 AN: 5768

European-Non Finnish (NFE) AF: 0.429 AC: 476989 AN: 1111940

Other (OTH) AF: 0.418 AC: 25244 AN: 60384

GnomAD4 genome AF: 0.438 AC: 66647 AN: 152000 Hom.: 14717 Cov.: 32 AF XY: 0.440 AC XY: 32684 AN XY: 74306

African (AFR) AF: 0.457 AC: 18957 AN: 41454

American (AMR) AF: 0.484 AC: 7404 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.397 AC: 1379 AN: 3470

East Asian (EAS) AF: 0.392 AC: 2010 AN: 5134

South Asian (SAS) AF: 0.397 AC: 1912 AN: 4820

European-Finnish (FIN) AF: 0.451 AC: 4768 AN: 10566

Middle Eastern (MID) AF: 0.422 AC: 124 AN: 294

European-Non Finnish (NFE) AF: 0.425 AC: 28864 AN: 67942

Other (OTH) AF: 0.437 AC: 924 AN: 2116

Alfa AF: 0.429 Hom.: 51456

Bravo AF: 0.442

Asia WGS AF: 0.387 AC: 1351 AN: 3478

EpiCase AF: 0.421

EpiControl AF: 0.418

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	-0.61
CADD	Benign	9.8
DANN	Benign	0.71
PhyloP100		0.54
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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: rs2287363; hg19: chr9-131767668; COSMIC: COSV65330746; COSMIC: COSV65330746;