rs2287363

chr9-129005389-A-Cchr9-129005389-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_015354.3(NUP188):c.4596A>C(p.Ser1532=) 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:3
• Conservation: PhyloP100: 0.539

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]

LOC101929314 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -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 id 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/exons	MANE	UniProt
NUP188	NM_015354.3	c.4596A>C	p.Ser1532=	synonymous_variant	40/44	ENST00000372577.2
LOC101929314	XR_007061810.1	n.85-92T>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NUP188	ENST00000372577.2	c.4596A>C	p.Ser1532=	synonymous_variant	40/44	1	NM_015354.3	P1

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

GnomAD3 exomes AF: 0.435 AC: 108657 AN: 249614 Hom.: 23996 AF XY: 0.430 AC XY: 58104 AN XY: 135170

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 SAS exome AF: 0.403

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

Gnomad4 AFR exome AF: 0.473

Gnomad4 AMR exome AF: 0.512

Gnomad4 ASJ exome AF: 0.387

Gnomad4 EAS exome AF: 0.359

Gnomad4 SAS exome AF: 0.399

Gnomad4 FIN exome AF: 0.435

Gnomad4 NFE exome AF: 0.429

Gnomad4 OTH exome AF: 0.418

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

Gnomad4 AFR AF: 0.457

Gnomad4 AMR AF: 0.484

Gnomad4 ASJ AF: 0.397

Gnomad4 EAS AF: 0.392

Gnomad4 SAS AF: 0.397

Gnomad4 FIN AF: 0.451

Gnomad4 NFE AF: 0.425

Gnomad4 OTH AF: 0.437

Alfa AF: 0.427 Hom.: 33190

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:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 29, 2016

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

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 17, 2019

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). -

Sandestig-stefanova syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
Cadd	Benign	9.8
Dann	Benign	0.71

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

Publications

LitVar

Other links and lift over

dbSNP: rs2287363; hg19: chr9-131767668; COSMIC: COSV65330746; COSMIC: COSV65330746;