12-68690746-G-A

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PP3_StrongPP5_Very_Strong

The NM_020401.4(NUP107):c.303G>A(p.Met101Ile) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000821 in 1,461,574 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000082 ( 0 hom. )

Consequence

NUP107
NM_020401.4 missense, splice_region

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 6.32

Publications

5 publications found

Variant links:

Genes affected

NUP107 (HGNC:29914): (nucleoporin 107) This gene encodes a member of the nucleoporin family. The protein is localized to the nuclear rim and is an essential component of the nuclear pore complex (NPC). All molecules entering or leaving the nucleus either diffuse through or are actively transported by the NPC. Alternate transcriptional splice variants of this gene have been observed but have not been thoroughly characterized. [provided by RefSeq, Jul 2008]

NUP107 Gene-Disease associations (from GenCC):

Galloway-Mowat syndrome 7
Inheritance: AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
nephrotic syndrome, type 11
Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
ovarian dysgenesis 6
Inheritance: AR Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
46 XX gonadal dysgenesis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
familial idiopathic steroid-resistant nephrotic syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Galloway-Mowat syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

NUP107 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 12 ACMG points.

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 12-68690746-G-A is Pathogenic according to our data. Variant chr12-68690746-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 183304.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020401.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NUP107	NM_020401.4	MANE Select	c.303G>A	p.Met101Ile	missense splice_region	Exon 4 of 28	NP_065134.1
	NUP107	NM_001330192.2		c.216G>A	p.Met72Ile	missense splice_region	Exon 4 of 28	NP_001317121.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
NUP107	ENST00000229179.9	TSL:1 MANE Select	c.303G>A	p.Met101Ile	missense splice_region	Exon 4 of 28	ENSP00000229179.4
NUP107	ENST00000535718.5	TSL:1	n.303G>A		splice_region non_coding_transcript_exon	Exon 4 of 25	ENSP00000445567.1
NUP107	ENST00000539906.5	TSL:2	c.216G>A	p.Met72Ile	missense splice_region	Exon 4 of 28	ENSP00000441448.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000399

AC:

AN:

250664

AF XY:

0.00000738

show subpopulations

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:

0.00000821

AC:

AN:

1461574

Hom.:

Cov.:

AF XY:

0.00000825

AC XY:

AN XY:

727080

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33464

American (AMR)

AF:

0.00

AC:

AN:

44666

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26126

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.000128

AC:

AN:

86196

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53404

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111874

Other (OTH)

AF:

0.00

AC:

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.446

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Jun 29, 2024

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; RNA studies demonstrate a damaging effect that leads to decreased protein expression (PMID: 28280135); This variant is associated with the following publications: (PMID: 38136965, 28117080, 28280135, 25558065, 30179222)

Feb 01, 2019

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Galloway-Mowat syndrome 7

Pathogenic:2

Jan 13, 2015

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

Jul 09, 2019

SIB Swiss Institute of Bioinformatics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:curation

This variant is interpreted as a Pathogenic for Galloway-Mowat syndrome 7. The following ACMG Tag(s) were applied: PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PS3 => Well-established functional studies show a deleterious effect (PMID:30179222). PP1-Strong => PP1 upgraded in strength to Strong (PMID:28280135; 30179222; 25558065). PM3 =>Multiple unrelated affected individuals homozygous for the variant (PMID:28280135; 30179222; 25558065; 28117080)

Global developmental delay;C3554634:Light complexion;CN228292:Early onset focal segmental glomerulosclerosis

Pathogenic:1

Dec 01, 2014

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:research

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

-0.027

BayesDel_noAF

Benign

-0.18

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.13

Eigen

Benign

0.064

Eigen_PC

Uncertain

0.25

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.52

M_CAP

Benign

0.050

MetaRNN

Benign

0.22

MetaSVM

Benign

-0.94

MutationAssessor

Benign

1.9

PhyloP100

6.3

PrimateAI

Benign

0.43

PROVEAN

Benign

-1.2

REVEL

Benign

0.068

Sift

Uncertain

0.025

Sift4G

Benign

0.10

Polyphen

0.0020

Vest4

0.54

MutPred

0.30

Gain of sheet (P = 0.039)

MVP

0.36

MPC

0.28

ClinPred

0.46

GERP RS

5.6

RBP_binding_hub_radar

0.77

RBP_regulation_power_radar

2.5

Varity_R

0.41

gMVP

0.42

Mutation Taster

=12/88

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

1.0

SpliceAI score (max)

0.59

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.59

Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over