rs4740559

Variant names:

• chr9-14130240-C-T
• rs4740559
• NM_001190737.2:c.926-4474G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001369458.1(NFIB):​c.992-4474G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.175 in 152,082 control chromosomes in the GnomAD database, including 2,588 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.17 (2588 hom., cov: 32)
• Consequence: NFIB NM_001369458.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.560
• 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.34 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001369458.1. 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.926-4474G>A		intron	N/A	NP_001177666.1
	NFIB	NM_001369458.1		c.992-4474G>A		intron	N/A	NP_001356387.1
	NFIB	NM_001369459.1		c.992-4474G>A		intron	N/A	NP_001356388.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NFIB	ENST00000380953.6	TSL:1 MANE Select	c.926-4474G>A		intron	N/A	ENSP00000370340.1
	NFIB	ENST00000380959.7	TSL:1	c.926-4474G>A		intron	N/A	ENSP00000370346.3
	NFIB	ENST00000543693.5	TSL:1	c.170-4474G>A		intron	N/A	ENSP00000442888.1

Frequencies

GnomAD3 genomes AF: 0.175 AC: 26569 AN: 151964 Hom.: 2586 Cov.: 32

Gnomad AFR AF: 0.184

Gnomad AMI AF: 0.157

Gnomad AMR AF: 0.257

Gnomad ASJ AF: 0.219

Gnomad EAS AF: 0.188

Gnomad SAS AF: 0.354

Gnomad FIN AF: 0.112

Gnomad MID AF: 0.209

Gnomad NFE AF: 0.144

Gnomad OTH AF: 0.197

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.175 AC: 26591 AN: 152082 Hom.: 2588 Cov.: 32 AF XY: 0.178 AC XY: 13203 AN XY: 74328

African (AFR) AF: 0.184 AC: 7631 AN: 41484

American (AMR) AF: 0.257 AC: 3929 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.219 AC: 762 AN: 3472

East Asian (EAS) AF: 0.189 AC: 973 AN: 5156

South Asian (SAS) AF: 0.354 AC: 1709 AN: 4822

European-Finnish (FIN) AF: 0.112 AC: 1190 AN: 10578

Middle Eastern (MID) AF: 0.204 AC: 60 AN: 294

European-Non Finnish (NFE) AF: 0.144 AC: 9785 AN: 67984

Other (OTH) AF: 0.194 AC: 409 AN: 2112

Alfa AF: 0.167 Hom.: 339

Bravo AF: 0.184

Asia WGS AF: 0.288 AC: 1001 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	3.1
DANN	Benign	0.71
PhyloP100		-0.56
Mutation Taster		=100/0	polymorphism (auto)

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: rs4740559; hg19: chr9-14130239;