rs1554639173

Positions:

• chr9-14120608-AGTTCGAGTTGAGAT-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_001190737.2(NFIB):​c.1063_1076delATCTCAACTCGAAC​(p.Ile355fs) variant causes a frameshift, splice region 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 Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NFIB NM_001190737.2 frameshift, splice_region
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 9.13

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 9-14120608-AGTTCGAGTTGAGAT-A is Pathogenic according to our data. Variant chr9-14120608-AGTTCGAGTTGAGAT-A is described in ClinVar as [Pathogenic]. Clinvar id is 560029.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-14120608-AGTTCGAGTTGAGAT-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NFIB	NM_001190737.2	c.1063_1076delATCTCAACTCGAAC	p.Ile355fs	frameshift_variant, splice_region_variant	8/11	ENST00000380953.6	NP_001177666.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NFIB	ENST00000380953.6	c.1063_1076delATCTCAACTCGAAC	p.Ile355fs	frameshift_variant, splice_region_variant	8/11	1	NM_001190737.2	ENSP00000370340.1

Frequencies

GnomAD3 genomes Cov.: 32

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

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Macrocephaly;C3714756:Intellectual disability Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Department of Human Genetics, University Hospital Magdeburg

-

- -

Macrocephaly, acquired, with impaired intellectual development Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 23, 2019

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1554639173; hg19: chr9-14120607;