chr9-14120618-G-A

Position:

• chr9-14120618-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001190737.2(NFIB):​c.1067C>T​(p.Ser356Leu) variant causes a missense 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: NFIB NM_001190737.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NFIB	NM_001190737.2	c.1067C>T	p.Ser356Leu	missense_variant	8/11	ENST00000380953.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NFIB	ENST00000380953.6	c.1067C>T	p.Ser356Leu	missense_variant	8/11	1	NM_001190737.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Macrocephaly;C3714756:Intellectual disability Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Department of Human Genetics, University Hospital Magdeburg

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.13	.;T;.;T;T;T;.;.;.;.;.;.;T;T;T
Eigen	Uncertain	0.68
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.97	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.033	D
MetaRNN	Uncertain	0.58	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.69	T
MutationAssessor	Benign	1.3	.;L;L;.;.;.;.;.;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-1.4	N;N;N;N;N;N;.;.;.;.;.;.;.;N;N
REVEL	Uncertain	0.34
Sift	Uncertain	0.0010	D;D;D;D;D;D;.;.;.;.;.;.;.;D;D
Sift4G	Benign	0.076	T;D;D;D;D;D;.;.;.;.;.;.;.;D;T
Polyphen		0.98	.;D;.;.;.;D;.;.;.;.;.;.;.;.;.
Vest4		0.72
MutPred		0.45		.;Loss of glycosylation at S356 (P = 0.0018);Loss of glycosylation at S356 (P = 0.0018);Loss of glycosylation at S356 (P = 0.0018);Loss of glycosylation at S356 (P = 0.0018);Loss of glycosylation at S356 (P = 0.0018);.;.;.;.;Loss of glycosylation at S356 (P = 0.0018);.;.;.;.;
MVP		0.21
MPC		1.9
ClinPred		0.92	D
GERP RS		5.3
Varity_R		0.52
gMVP		0.35

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1554639196; hg19: chr9-14120617;