1-93547419-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001164473.3(FNBP1L):c.1480C>G(p.Leu494Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000142 in 1,405,274 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: FNBP1L NM_001164473.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.94

Genes affected

FNBP1L (HGNC:20851): (formin binding protein 1 like) The protein encoded by this gene binds to both CDC42 and N-WASP. This protein promotes CDC42-induced actin polymerization by activating the N-WASP-WIP complex and, therefore, is involved in a pathway that links cell surface signals to the actin cytoskeleton. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18054569).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FNBP1L	NM_001164473.3	c.1480C>G	p.Leu494Val	missense_variant	14/17	ENST00000271234.13
FNBP1L	NM_001024948.3	c.1306C>G	p.Leu436Val	missense_variant	12/14
FNBP1L	NM_017737.5	c.1306C>G	p.Leu436Val	missense_variant	12/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FNBP1L	ENST00000271234.13	c.1480C>G	p.Leu494Val	missense_variant	14/17	5	NM_001164473.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000601 AC: 1 AN: 166372 Hom.: 0 AF XY: 0.0000114 AC XY: 1 AN XY: 87508

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.0000150

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000142 AC: 2 AN: 1405274 Hom.: 0 Cov.: 30 AF XY: 0.00000288 AC XY: 2 AN XY: 693680

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000185

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000312 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000881 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

Aug 10, 2021

The c.1480C>G (p.L494V) alteration is located in exon 14 (coding exon 14) of the FNBP1L gene. This alteration results from a C to G substitution at nucleotide position 1480, causing the leucine (L) at amino acid position 494 to be replaced by a valine (V). 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	0.091
BayesDel_addAF	Benign	-0.0099	T
BayesDel_noAF	Benign	-0.25
Cadd	Benign	22
Dann	Uncertain	1.0
DEOGEN2	Benign	0.037	T;.;.;.
Eigen	Benign	0.15
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D;D;D;D
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.18	T;T;T;T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	1.1	L;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	0.10	N;N;.;.
REVEL	Benign	0.24
Sift	Benign	0.51	T;T;.;.
Sift4G	Benign	0.53	T;T;T;T
Polyphen		0.95, 0.21	.;P;.;B
Vest4		0.25
MutPred		0.23		Gain of MoRF binding (P = 0.0947);.;Gain of MoRF binding (P = 0.0947);.;
MVP		0.56
MPC		0.59
ClinPred		0.43	T
GERP RS		5.8
Varity_R		0.095
gMVP		0.22

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: rs757010427; hg19: chr1-94012976;