chr9-14307175-T-C

Variant names:

• chr9-14307175-T-C
• rs1554709662
• NM_001190737.2:c.376A>G

Variant summary

Our verdict is Pathogenic. The variant received 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
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• macrocephaly, acquired, with impaired intellectual development

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Illumina, G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 560026.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001190737.2. 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
	NFIB	NM_001190737.2	MANE Select	c.376A>G	p.Lys126Glu	missense	Exon 2 of 11	NP_001177666.1
	NFIB	NM_001369458.1		c.442A>G	p.Lys148Glu	missense	Exon 2 of 12	NP_001356387.1
	NFIB	NM_001369459.1		c.442A>G	p.Lys148Glu	missense	Exon 2 of 12	NP_001356388.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NFIB	ENST00000380953.6	TSL:1 MANE Select	c.376A>G	p.Lys126Glu	missense	Exon 2 of 11	ENSP00000370340.1
	NFIB	ENST00000380959.7	TSL:1	c.376A>G	p.Lys126Glu	missense	Exon 2 of 9	ENSP00000370346.3
	NFIB	ENST00000380921.3	TSL:1	c.376A>G	p.Lys126Glu	missense	Exon 2 of 3	ENSP00000370308.3

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

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, PP3, PM1-Supporting, PS3-Moderate, PS2-Moderate.

Jan 23, 2019

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Jun 01, 2022

Solve-RD Consortium

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: provider interpretation

Variant confirmed as disease-causing by referring clinical team

Macrocephaly;C3714756:Intellectual disability Pathogenic:1

Department of Human Genetics, University Hospital Magdeburg

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

Marfanoid habitus and intellectual disability Pathogenic:1

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

not provided Pathogenic:1

Jun 08, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 v4.9

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
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Uncertain	0.50	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		8.0
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-3.5	D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.98	D
Vest4		0.98
MutPred		0.59		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
Mutation Taster		=1/99	disease causing (ClinVar)

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

Other links and lift over

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