11-47779197-A-G

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP6

The NM_015231.3(NUP160):c.4120-3T>C variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000519 in 1,594,308 control chromosomes in the GnomAD database, including 1 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00055 (1 hom.)
• Consequence: NUP160 NM_015231.3 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0001096
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 0.424

Genes affected

NUP160 (HGNC:18017): (nucleoporin 160) A structural constituent of nuclear pore. Involved in mRNA export from nucleus and nephron development. Part of nuclear pore outer ring. Colocalizes with kinetochore. Implicated in nephrotic syndrome type 19. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 11-47779197-A-G is Benign according to our data. Variant chr11-47779197-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2188854.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NUP160	NM_015231.3	c.4120-3T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000378460.7
NUP160	NR_134636.3	n.4167-3T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NUP160	ENST00000378460.7	c.4120-3T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_015231.3	P1
NUP160	ENST00000530326.5	c.3884-33T>C		intron_variant		5
NUP160	ENST00000694866.1	c.4222-3T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant

Frequencies

GnomAD3 genomes AF: 0.000243 AC: 37 AN: 152214 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000412

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000304 AC: 75 AN: 247076 Hom.: 0 AF XY: 0.000284 AC XY: 38 AN XY: 133762

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000547

Gnomad SAS exome AF: 0.0000335

Gnomad FIN exome AF: 0.000650

Gnomad NFE exome AF: 0.000474

Gnomad OTH exome AF: 0.000497

GnomAD4 exome AF: 0.000549 AC: 791 AN: 1442094 Hom.: 1 Cov.: 25 AF XY: 0.000516 AC XY: 371 AN XY: 718588

Gnomad4 AFR exome AF: 0.0000912

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.0000117

Gnomad4 FIN exome AF: 0.000919

Gnomad4 NFE exome AF: 0.000610

Gnomad4 OTH exome AF: 0.00116

GnomAD4 genome AF: 0.000243 AC: 37 AN: 152214 Hom.: 0 Cov.: 32 AF XY: 0.000256 AC XY: 19 AN XY: 74362

Gnomad4 AFR AF: 0.000121

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000283

Gnomad4 NFE AF: 0.000412

Gnomad4 OTH AF: 0.000479

Alfa AF: 0.000507 Hom.: 0

Bravo AF: 0.000215

EpiCase AF: 0.000709

EpiControl AF: 0.000296

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

May 19, 2022

This sequence change falls in intron 35 of the NUP160 gene. It does not directly change the encoded amino acid sequence of the NUP160 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs201495092, gnomAD 0.06%). This variant has not been reported in the literature in individuals affected with NUP160-related conditions. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. 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. -

NUP160-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 14, 2019

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

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
Cadd	Benign	4.3
Dann	Benign	0.85

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00011
dbscSNV1_RF	Benign	0.036
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

Publications

LitVar

Other links and lift over

dbSNP: rs201495092; hg19: chr11-47800749;