NM_001190737.2:c.1331G>A

Variant names:

• chr9-14116261-C-T
• NM_001190737.2:c.1331G>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP5_Moderate

The NM_001190737.2(NFIB):​c.1331G>A​(p.Arg444Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000721 in 1,386,108 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: NFIB NM_001190737.2 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.57
• 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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 9-14116261-C-T is Pathogenic according to our data. Variant chr9-14116261-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3900512.Status of the report is criteria_provided_single_submitter, 1 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NFIB	NM_001190737.2	MANE Select	c.1331G>A	p.Arg444Gln	missense	Exon 9 of 11	NP_001177666.1	O00712-5
	NFIB	NM_001369458.1		c.1397G>A	p.Arg466Gln	missense	Exon 9 of 12	NP_001356387.1
	NFIB	NM_001369459.1		c.1397G>A	p.Arg466Gln	missense	Exon 9 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.1331G>A	p.Arg444Gln	missense	Exon 9 of 11	ENSP00000370340.1	O00712-5
	NFIB	ENST00000543693.5	TSL:1	c.575G>A	p.Arg192Gln	missense	Exon 8 of 11	ENSP00000442888.1	O00712-6
	NFIB	ENST00000380959.7	TSL:1	c.1245+4179G>A		intron	N/A	ENSP00000370346.3	O00712-1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.21e-7 AC: 1 AN: 1386108 Hom.: 0 Cov.: 31 AF XY: 0.00000146 AC XY: 1 AN XY: 683322

African (AFR) AF: 0.00 AC: 0 AN: 31302

American (AMR) AF: 0.00 AC: 0 AN: 34128

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25020

East Asian (EAS) AF: 0.00 AC: 0 AN: 34900

South Asian (SAS) AF: 0.00 AC: 0 AN: 76996

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48262

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5674

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1072230

Other (OTH) AF: 0.0000174 AC: 1 AN: 57596

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.081	T
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.012	T
MetaRNN	Uncertain	0.66	D
MetaSVM	Benign	-0.72	T
PhyloP100		7.6
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-2.0	N
REVEL	Uncertain	0.38
Sift	Benign	0.046	D
Sift4G	Benign	0.36	T
Vest4		0.75
MutPred		0.60		Loss of methylation at R444 (P = 0.0218)
MVP		0.42
MPC		2.1
ClinPred		0.97	D
GERP RS		5.9
gMVP		0.57
Mutation Taster		=28/72	disease causing

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

hg19: chr9-14116260;