17-75928187-C-G

Variant summary

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

The NM_001319193.2(FBF1):c.286G>C(p.Asp96His) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,568 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: FBF1 NM_001319193.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.96

Genes affected

FBF1 (HGNC:24674): (Fas binding factor 1) Involved in apical junction assembly and establishment of epithelial cell polarity. Acts upstream of or within cilium assembly. Located in centriole; centrosome; and spindle pole. Part of ciliary transition fiber. Colocalizes with apical junction complex and keratin filament. [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
FBF1	NM_001319193.2	c.286G>C	p.Asp96His	missense_variant	8/30	ENST00000636174.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FBF1	ENST00000636174.2	c.286G>C	p.Asp96His	missense_variant	8/30	5	NM_001319193.2	P2
FBF1	ENST00000586717.5	c.244G>C	p.Asp82His	missense_variant	7/29	5		A2
FBF1	ENST00000319129.10	c.121G>C	p.Asp41His	missense_variant	3/25	5
FBF1	ENST00000585990.5	n.364G>C		non_coding_transcript_exon_variant	7/28	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000803 AC: 2 AN: 249046 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135158

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000580

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461568 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727054

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000827 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 16, 2021

The c.244G>C (p.D82H) alteration is located in exon 7 (coding exon 6) of the FBF1 gene. This alteration results from a G to C substitution at nucleotide position 244, causing the aspartic acid (D) at amino acid position 82 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.0039	T
BayesDel_noAF	Uncertain	-0.070
Cadd	Uncertain	24
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.46	T;T;.
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.87	D;D;D
M_CAP	Benign	0.050	D
MetaRNN	Uncertain	0.52	D;D;D
MetaSVM	Uncertain	0.0018	D
MutationAssessor	Uncertain	2.5	M;.;.
MutationTaster	Benign	0.99	D;D;D
PrimateAI	Uncertain	0.52	T
Sift4G	Pathogenic	0.0	D;D;.
Polyphen		1.0	D;.;D
Vest4		0.81
MutPred		0.21		Loss of ubiquitination at K79 (P = 0.1264);.;.;
MVP		0.60
ClinPred		0.94	D
GERP RS		5.1
Varity_R		0.18
gMVP		0.55

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs746459524; hg19: chr17-73924268;