rs1230522675

Variant names:

• chr11-47785062-C-T
• rs1230522675
• NM_015231.3:c.3748G>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_015231.3(NUP160):​c.3748G>A​(p.Ala1250Thr) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000741 in 1,349,050 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 27)
  • Exomes 𝑓: 7.4e-7 (0 hom.)
• Consequence: NUP160 NM_015231.3 missense, splice_region
• Scores: Splicing: ADA: 0.9920
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.45
• Publications: 0 publications found

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]

NUP160 Gene-Disease associations (from GenCC):

• nephrotic syndrome, type 19

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• familial idiopathic steroid-resistant nephrotic syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NUP160	NM_015231.3	c.3748G>A	p.Ala1250Thr	missense_variant, splice_region_variant	Exon 33 of 36	ENST00000378460.7	NP_056046.2
NUP160	NR_134636.3	n.3795G>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 33 of 36

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NUP160	ENST00000378460.7	c.3748G>A	p.Ala1250Thr	missense_variant, splice_region_variant	Exon 33 of 36	1	NM_015231.3	ENSP00000367721.3
NUP160	ENST00000694866.1	c.3850G>A	p.Ala1284Thr	missense_variant, splice_region_variant	Exon 33 of 36			ENSP00000511549.1
NUP160	ENST00000530326.5	c.3742G>A	p.Ala1248Thr	missense_variant, splice_region_variant	Exon 33 of 34	5		ENSP00000433590.2
NUP160	ENST00000532773.1	n.195G>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 3 of 3	5

Frequencies

GnomAD3 genomes Cov.: 27

GnomAD2 exomes AF: 0.00 AC: 0 AN: 196068 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.41e-7 AC: 1 AN: 1349050 Hom.: 0 Cov.: 28 AF XY: 0.00000150 AC XY: 1 AN XY: 667016

African (AFR) AF: 0.00 AC: 0 AN: 30570

American (AMR) AF: 0.00 AC: 0 AN: 33090

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21952

East Asian (EAS) AF: 0.00 AC: 0 AN: 35604

South Asian (SAS) AF: 0.00 AC: 0 AN: 67508

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50206

Middle Eastern (MID) AF: 0.000188 AC: 1 AN: 5310

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1049958

Other (OTH) AF: 0.00 AC: 0 AN: 54852

GnomAD4 genome Cov.: 27

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 01, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3850G>A (p.A1284T) alteration is located in exon 33 (coding exon 33) of the NUP160 gene. This alteration results from a G to A substitution at nucleotide position 3850, causing the alanine (A) at amino acid position 1284 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Uncertain	0.066	T
BayesDel_noAF	Benign	-0.14
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.041	T
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.34	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		5.5
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.14
Sift	Benign	0.049	D
Sift4G	Benign	0.088	T
Polyphen		0.96	D
Vest4		0.29
MutPred		0.22		Gain of relative solvent accessibility (P = 0.09);
MVP		0.43
MPC		0.44
ClinPred		0.84	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.24
gMVP		0.45
Mutation Taster		=43/57	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Pathogenic	0.87
SpliceAI score (max)		0.19		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: rs1230522675; hg19: chr11-47806614;