9-14120480-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001190737.2(NFIB):c.1205A>G(p.Tyr402Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,864 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: NFIB NM_001190737.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.31

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NFIB	NM_001190737.2	c.1205A>G	p.Tyr402Cys	missense_variant	8/11	ENST00000380953.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NFIB	ENST00000380953.6	c.1205A>G	p.Tyr402Cys	missense_variant	8/11	1	NM_001190737.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461864 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727232

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 01, 2022

The c.1205A>G (p.Y402C) alteration is located in exon 8 (coding exon 8) of the NFIB gene. This alteration results from a A to G substitution at nucleotide position 1205, causing the tyrosine (Y) at amino acid position 402 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
Cadd	Pathogenic	30
Dann	Uncertain	1.0
Eigen	Uncertain	0.63
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.96	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.075	D
MetaRNN	Uncertain	0.63	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.69	T
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-3.6	D;N;D;D;D;N;.;.;.;.;.;.;.;N;D
REVEL	Uncertain	0.50
Sift	Uncertain	0.0010	D;D;D;D;D;D;.;.;.;.;.;.;.;D;D
Sift4G	Benign	0.17	T;D;D;D;D;D;.;.;.;.;.;.;.;D;T
Polyphen		1.0	.;D;.;.;.;D;.;.;.;.;.;.;.;.;.
Vest4		0.97
MutPred		0.61		.;Loss of phosphorylation at Y402 (P = 0.0243);Loss of phosphorylation at Y402 (P = 0.0243);Loss of phosphorylation at Y402 (P = 0.0243);Loss of phosphorylation at Y402 (P = 0.0243);Loss of phosphorylation at Y402 (P = 0.0243);.;.;.;.;Loss of phosphorylation at Y402 (P = 0.0243);.;.;.;.;
MVP		0.52
MPC		2.2
ClinPred		0.98	D
GERP RS		5.7
Varity_R		0.55
gMVP		0.72

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: rs1586826467; hg19: chr9-14120479;