rs764333096

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_001190737.2(NFIB):​c.265C>T​(p.Arg89*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 32)

Consequence

NFIB
NM_001190737.2 stop_gained

Scores

4
2
1

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 10.0
Variant links:
Genes affected
NFIB (HGNC:7785): (nuclear factor I B) Enables DNA-binding transcription activator activity, RNA polymerase II-specific; RNA polymerase II cis-regulatory region sequence-specific DNA binding activity; and transcription regulator inhibitor activity. Involved in brain development; negative regulation of DNA binding activity; and regulation of transcription by RNA polymerase II. Located in fibrillar center and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 9-14307286-G-A is Pathogenic according to our data. Variant chr9-14307286-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 424344.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-14307286-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
NFIBNM_001190737.2 linkc.265C>T p.Arg89* stop_gained Exon 2 of 11 ENST00000380953.6 NP_001177666.1 O00712-5

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
NFIBENST00000380953.6 linkc.265C>T p.Arg89* stop_gained Exon 2 of 11 1 NM_001190737.2 ENSP00000370340.1 O00712-5

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
33
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Macrocephaly, acquired, with impaired intellectual development Pathogenic:5
Jan 30, 2020
Genomic Medicine Lab, University of California San Francisco
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jan 23, 2019
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

Aug 25, 2019
Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City
Significance: Likely pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Oct 02, 2019
SIB Swiss Institute of Bioinformatics
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: curation

This variant is interpreted as a Likely pathogenic for Macrocephaly, acquired, with impaired intellectual development, autosomal dominant. The following ACMG Tag(s) were applied: PM2, PVS1. -

Jul 31, 2020
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Variant summary: NFIB c.265C>T (p.Arg89X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 251404 control chromosomes (gnomAD). c.265C>T has been reported in the literature in at least one individual affected with macrocephaly, developmental delays, and mild-moderate intellectual disability (e.g. Schanze_2018). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=1) and likely pathogenic/pathogenic (n=3). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Macrocephaly;C3714756:Intellectual disability Pathogenic:1
-
Department of Human Genetics, University Hospital Magdeburg
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: research

- -

not provided Pathogenic:1
Mar 14, 2023
GeneDx
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 32902921, 33130023, 30388402) -

Macrocephaly Pathogenic:1
Oct 04, 2024
Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: research

PVS1,PM2 -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.57
D
BayesDel_noAF
Pathogenic
0.59
CADD
Pathogenic
57
DANN
Uncertain
1.0
Eigen
Pathogenic
1.1
Eigen_PC
Pathogenic
0.96
FATHMM_MKL
Uncertain
0.97
D
Vest4
0.87
GERP RS
5.7

Splicing

Name
Calibrated prediction
Score
Prediction
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs764333096; hg19: chr9-14307285; API