dbSNP rs1554639173: NFIB:p.Ile355SerfsTer48 (chr9-14120608-AGTTCGAGTTGAGAT-A) – ACMG Classification: Pathogenic (10 pts)

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1PP5_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

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 9.13

Publications

0 publications found

Variant links:

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

NFIB links:

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ACMG classification

Classification was made for transcript

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.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NFIB	NM_001190737.2	MANE Select	c.1063_1076delATCTCAACTCGAAC	p.Ile355SerfsTer48	frameshift splice_region	Exon 8 of 11	NP_001177666.1	O00712-5
NFIB	NM_001369458.1		c.1129_1142delATCTCAACTCGAAC	p.Ile377SerfsTer48	frameshift splice_region	Exon 8 of 12	NP_001356387.1
NFIB	NM_001369459.1		c.1129_1142delATCTCAACTCGAAC	p.Ile377SerfsTer48	frameshift splice_region	Exon 8 of 12	NP_001356388.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NFIB	ENST00000380953.6	TSL:1 MANE Select	c.1063_1076delATCTCAACTCGAAC	p.Ile355SerfsTer48	frameshift splice_region	Exon 8 of 11	ENSP00000370340.1	O00712-5
NFIB	ENST00000380959.7	TSL:1	c.1063_1076delATCTCAACTCGAAC	p.Ile355SerfsTer48	frameshift splice_region	Exon 8 of 9	ENSP00000370346.3	O00712-1
NFIB	ENST00000543693.5	TSL:1	c.307_320delATCTCAACTCGAAC	p.Ile103SerfsTer48	frameshift splice_region	Exon 7 of 11	ENSP00000442888.1	O00712-6

Frequencies

GnomAD3 genomes

Cov.:

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

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Macrocephaly, acquired, with impaired intellectual development (1)

Macrocephaly;C3714756:Intellectual disability (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

9.1

Mutation Taster

=18/182

disease causing (ClinVar)

(source)

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over