9-14307175-T-C

Position:

• chr9-14307175-T-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2 PP3_Moderate PP5_Very_Strong

The NM_001190737.2(NFIB):​c.376A>G​(p.Lys126Glu) variant causes a missense 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 (★★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: NFIB NM_001190737.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 8.02

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]

NFIB (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.845
• PP5: Variant 9-14307175-T-C is Pathogenic according to our data. Variant chr9-14307175-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 560026.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-14307175-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NFIB	NM_001190737.2	c.376A>G	p.Lys126Glu	missense_variant	2/11	ENST00000380953.6	NP_001177666.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NFIB	ENST00000380953.6	c.376A>G	p.Lys126Glu	missense_variant	2/11	1	NM_001190737.2	ENSP00000370340.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Macrocephaly, acquired, with impaired intellectual development Pathogenic:3

Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 23, 2019	- -
Likely pathogenic, no assertion criteria provided	provider interpretation	Solve-RD Consortium	Jun 01, 2022	Variant confirmed as disease-causing by referring clinical team -
Likely pathogenic, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	Oct 02, 2019	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, PP3, PM1-Supporting, PS3-Moderate, PS2-Moderate. -

Macrocephaly;C3714756:Intellectual disability Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Department of Human Genetics, University Hospital Magdeburg

-

- -

Marfanoid habitus and intellectual disability Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

-

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jun 08, 2023

Published functional studies demonstrate a damaging effect as p.(K126E) caused significant reduction in luciferase activity compared to the wild type protein (Schanze et al., 2018); 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; This variant is associated with the following publications: (PMID: 30388402, 32277047) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.36
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.77	D;.;D;D;D;.;.;.;.;.;T;D;.;.
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.84	D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.50	D
MutationAssessor	Uncertain	2.4	M;M;.;.;.;.;.;.;.;.;.;.;.;.
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-3.5	D;D;D;D;D;.;.;.;.;.;D;D;.;.
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D;D;D;D;D;.;.;.;.;.;D;D;.;.
Sift4G	Pathogenic	0.0	D;D;D;D;D;.;.;.;.;.;D;D;D;.
Polyphen		0.98	D;.;.;.;D;.;.;.;.;.;.;.;.;.
Vest4		0.98
MutPred		0.59		Loss of MoRF binding (P = 6e-04);Loss of MoRF binding (P = 6e-04);Loss of MoRF binding (P = 6e-04);Loss of MoRF binding (P = 6e-04);Loss of MoRF binding (P = 6e-04);.;.;.;.;Loss of MoRF binding (P = 6e-04);.;Loss of MoRF binding (P = 6e-04);Loss of MoRF binding (P = 6e-04);.;
MVP		0.92
MPC		2.3
ClinPred		0.98	D
GERP RS		5.7
Varity_R		0.88
gMVP		0.99

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

Other links and lift over

dbSNP: rs1554709662; hg19: chr9-14307174; COSMIC: COSV66620569;