9-14116261-C-T

Variant names:

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

Variant summary

Our verdict is Uncertain significance. Variant got 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

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 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 id is 3900512.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NFIB	NM_001190737.2	c.1331G>A	p.Arg444Gln	missense_variant	Exon 9 of 11	ENST00000380953.6	NP_001177666.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NFIB	ENST00000380953.6	c.1331G>A	p.Arg444Gln	missense_variant	Exon 9 of 11	1	NM_001190737.2	ENSP00000370340.1

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

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: 0.00

Gnomad4 OTH exome AF: 0.0000174

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Nov 25, 2024

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.081	.;.;T;T;.;T
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D;D
M_CAP	Benign	0.012	T
MetaRNN	Uncertain	0.66	D;D;D;D;D;D
MetaSVM	Benign	-0.72	T
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-2.0	N;N;N;N;.;.
REVEL	Uncertain	0.38
Sift	Benign	0.046	D;T;D;D;.;.
Sift4G	Benign	0.36	T;D;D;D;.;.
Vest4		0.75
MutPred		0.60		.;Loss of methylation at R444 (P = 0.0218);Loss of methylation at R444 (P = 0.0218);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

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr9-14116260;