chr9-14120618-G-A

Variant names:

• chr9-14120618-G-A
• rs1554639196
• NM_001190737.2:c.1067C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001190737.2(NFIB):​c.1067C>T​(p.Ser356Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: NFIB NM_001190737.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.13
• Publications: 0 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):

• syndromic complex neurodevelopmental disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• macrocephaly, acquired, with impaired intellectual development

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NFIB	NM_001190737.2	MANE Select	c.1067C>T	p.Ser356Leu	missense	Exon 8 of 11	NP_001177666.1	O00712-5
	NFIB	NM_001369458.1		c.1133C>T	p.Ser378Leu	missense	Exon 8 of 12	NP_001356387.1
	NFIB	NM_001369459.1		c.1133C>T	p.Ser378Leu	missense	Exon 8 of 12	NP_001356388.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NFIB	ENST00000380953.6	TSL:1 MANE Select	c.1067C>T	p.Ser356Leu	missense	Exon 8 of 11	ENSP00000370340.1	O00712-5
	NFIB	ENST00000380959.7	TSL:1	c.1067C>T	p.Ser356Leu	missense	Exon 8 of 9	ENSP00000370346.3	O00712-1
	NFIB	ENST00000543693.5	TSL:1	c.311C>T	p.Ser104Leu	missense	Exon 7 of 11	ENSP00000442888.1	O00712-6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Macrocephaly;C3714756:Intellectual disability (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
PhyloP100		9.1
Varity_R		0.52
gMVP		0.35
Mutation Taster		=40/60	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs1554639196; hg19: chr9-14120617;