rs1554639173

Variant names:

• chr9-14120608-AGTTCGAGTTGAGAT-A
• rs1554639173
• NM_001190737.2:c.1063_1076delATCTCAACTCGAAC

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PP5_Moderate

The NM_001190737.2(NFIB):​c.1063_1076delATCTCAACTCGAAC​(p.Ile355SerfsTer48) variant causes a frameshift, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. 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
• 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):

• 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: Pathogenic. The variant received 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 9-14120608-AGTTCGAGTTGAGAT-A is Pathogenic according to our data. Variant chr9-14120608-AGTTCGAGTTGAGAT-A is described in ClinVar as Pathogenic. ClinVar VariationId is 560029.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.1063_1076delATCTCAACTCGAAC	p.Ile355SerfsTer48	frameshift_variant, splice_region_variant	Exon 8 of 11	ENST00000380953.6	NP_001177666.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NFIB	ENST00000380953.6	c.1063_1076delATCTCAACTCGAAC	p.Ile355SerfsTer48	frameshift_variant, splice_region_variant	Exon 8 of 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

-

Department of Human Genetics, University Hospital Magdeburg

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Macrocephaly, acquired, with impaired intellectual development Pathogenic:1

Jan 23, 2019

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.1
Mutation Taster		=18/182	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs1554639173; hg19: chr9-14120607;