NM_015354.3:c.4044+6A>C

Variant names:

• chr9-129001735-A-C
• rs12336276
• NM_015354.3:c.4044+6A>C

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.4044+6A>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.115 in 1,612,086 control chromosomes in the GnomAD database, including 14,930 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 0.17 (3237 hom., cov: 32)
  • Exomes 𝑓: 0.11 (11693 hom.)
• Consequence: NUP188 NM_015354.3 splice_region, intron
• Scores: Splicing: ADA: 0.0003852
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.06
• Publications: 5 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=-0.73).
• BP6: Variant 9-129001735-A-C is Benign according to our data. Variant chr9-129001735-A-C is described in ClinVar as Benign. ClinVar VariationId is 403265.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.333 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NUP188	NM_015354.3	c.4044+6A>C		splice_region_variant, intron_variant	Intron 35 of 43	ENST00000372577.2	NP_056169.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NUP188	ENST00000372577.2	c.4044+6A>C		splice_region_variant, intron_variant	Intron 35 of 43	1	NM_015354.3	ENSP00000361658.2
NUP188	ENST00000477069.5	n.2012+6A>C		splice_region_variant, intron_variant	Intron 16 of 18	1
NUP188	ENST00000487952.1	n.412A>C		non_coding_transcript_exon_variant	Exon 2 of 2	2

Frequencies

GnomAD3 genomes AF: 0.174 AC: 26379 AN: 151972 Hom.: 3233 Cov.: 32

Gnomad AFR AF: 0.337

Gnomad AMI AF: 0.0428

Gnomad AMR AF: 0.118

Gnomad ASJ AF: 0.0888

Gnomad EAS AF: 0.309

Gnomad SAS AF: 0.238

Gnomad FIN AF: 0.118

Gnomad MID AF: 0.158

Gnomad NFE AF: 0.0872

Gnomad OTH AF: 0.143

GnomAD2 exomes AF: 0.142 AC: 35111 AN: 247670 AF XY: 0.141

Gnomad AFR exome AF: 0.340

Gnomad AMR exome AF: 0.110

Gnomad ASJ exome AF: 0.0964

Gnomad EAS exome AF: 0.314

Gnomad FIN exome AF: 0.115

Gnomad NFE exome AF: 0.0851

Gnomad OTH exome AF: 0.121

GnomAD4 exome AF: 0.109 AC: 159741 AN: 1459996 Hom.: 11693 Cov.: 33 AF XY: 0.112 AC XY: 81171 AN XY: 726318

African (AFR) AF: 0.342 AC: 11423 AN: 33446

American (AMR) AF: 0.110 AC: 4882 AN: 44484

Ashkenazi Jewish (ASJ) AF: 0.0943 AC: 2460 AN: 26086

East Asian (EAS) AF: 0.312 AC: 12353 AN: 39628

South Asian (SAS) AF: 0.220 AC: 18950 AN: 86054

European-Finnish (FIN) AF: 0.107 AC: 5665 AN: 52932

Middle Eastern (MID) AF: 0.126 AC: 721 AN: 5736

European-Non Finnish (NFE) AF: 0.0860 AC: 95624 AN: 1111278

Other (OTH) AF: 0.127 AC: 7663 AN: 60352

GnomAD4 genome AF: 0.174 AC: 26408 AN: 152090 Hom.: 3237 Cov.: 32 AF XY: 0.177 AC XY: 13127 AN XY: 74342

African (AFR) AF: 0.337 AC: 13991 AN: 41472

American (AMR) AF: 0.118 AC: 1807 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0888 AC: 308 AN: 3468

East Asian (EAS) AF: 0.309 AC: 1588 AN: 5142

South Asian (SAS) AF: 0.238 AC: 1146 AN: 4824

European-Finnish (FIN) AF: 0.118 AC: 1247 AN: 10604

Middle Eastern (MID) AF: 0.156 AC: 46 AN: 294

European-Non Finnish (NFE) AF: 0.0872 AC: 5931 AN: 67978

Other (OTH) AF: 0.145 AC: 305 AN: 2110

Alfa AF: 0.161 Hom.: 1888

Bravo AF: 0.178

Asia WGS AF: 0.265 AC: 921 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Feb 25, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

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

Nov 14, 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).

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	-0.73
CADD	Benign	8.6
DANN	Benign	0.78
PhyloP100		1.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00039
dbscSNV1_RF	Benign	0.010
SpliceAI score (max)		0.0		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: rs12336276; hg19: chr9-131764014; COSMIC: COSV65361499; COSMIC: COSV65361499;