rs1554709683

chr9-14307210-T-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Moderate

The NM_001190737.2(NFIB):c.341A>C(p.Lys114Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K114E) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: NFIB NM_001190737.2 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 8.02

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 Pathogenic. Variant got 10 ACMG points.

• PM1: In a DNA_binding_region CTF/NF-I (size 194) in uniprot entity NFIB_HUMAN there are 9 pathogenic changes around while only 2 benign (82%) in NM_001190737.2
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr9-14307211-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1806041.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.872
• PP5: Variant 9-14307210-T-G is Pathogenic according to our data. Variant chr9-14307210-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 560025.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-14307210-T-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NFIB	NM_001190737.2	c.341A>C	p.Lys114Thr	missense_variant	2/11	ENST00000380953.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NFIB	ENST00000380953.6	c.341A>C	p.Lys114Thr	missense_variant	2/11	1	NM_001190737.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

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

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- -

Macrocephaly, acquired, with impaired intellectual development Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 23, 2019

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.16
Cadd	Pathogenic	34
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.76	D;.;D;D;D;.;.;.;.;.;T;D;.;.
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	1.0	D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.87	D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.41	D
MutationAssessor	Uncertain	2.4	M;M;.;.;.;.;.;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-5.3	D;D;D;D;D;.;.;.;.;.;D;D;.;.
REVEL	Pathogenic	0.85
Sift	Pathogenic	0.0	D;D;D;D;D;.;.;.;.;.;D;D;.;.
Sift4G	Pathogenic	0.0	D;D;D;D;D;.;.;.;.;.;D;D;D;.
Polyphen		0.99	D;.;.;.;D;.;.;.;.;.;.;.;.;.
Vest4		0.84
MutPred		0.51		Loss of catalytic residue at K114 (P = 0.0118);Loss of catalytic residue at K114 (P = 0.0118);Loss of catalytic residue at K114 (P = 0.0118);Loss of catalytic residue at K114 (P = 0.0118);Loss of catalytic residue at K114 (P = 0.0118);.;.;.;.;Loss of catalytic residue at K114 (P = 0.0118);.;Loss of catalytic residue at K114 (P = 0.0118);Loss of catalytic residue at K114 (P = 0.0118);.;
MVP		0.59
MPC		2.2
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.86
gMVP		0.97

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: rs1554709683; hg19: chr9-14307209;