1-93549374-T-G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001164473.3(FNBP1L):c.1599T>G(p.Asp533Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000149 in 1,612,588 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

FNBP1L
NM_001164473.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.617

Variant links:

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]

FNBP1L links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.11061269).

BS2

High AC in GnomAdExome at 14 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
FNBP1L	NM_001164473.3 linkuse as main transcript	c.1599T>G	p.Asp533Glu	missense_variant	15/17	ENST00000271234.13
FNBP1L	NM_001024948.3 linkuse as main transcript	c.1425T>G	p.Asp475Glu	missense_variant	13/14
FNBP1L	NM_017737.5 linkuse as main transcript	c.1425T>G	p.Asp475Glu	missense_variant	13/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FNBP1L	ENST00000271234.13 linkuse as main transcript	c.1599T>G	p.Asp533Glu	missense_variant	15/17	5	NM_001164473.3		Q5T0N5-1
FNBP1L	ENST00000260506.12 linkuse as main transcript	c.1425T>G	p.Asp475Glu	missense_variant	13/14	1		P4	Q5T0N5-4
FNBP1L	ENST00000370253.6 linkuse as main transcript	c.1425T>G	p.Asp475Glu	missense_variant	13/15	5		A1	Q5T0N5-3
FNBP1L	ENST00000424449.2 linkuse as main transcript	c.1137T>G	p.Asp379Glu	missense_variant	10/12	2

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000565

AC:

AN:

247690

Hom.:

AF XY:

0.0000446

AC XY:

AN XY:

134390

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000294

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:

0.000666

GnomAD4 exome

AF:

0.0000144

AC:

AN:

1460424

Hom.:

Cov.:

AF XY:

0.00000826

AC XY:

AN XY:

726486

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000360

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152164

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74340

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000340

ExAC

AF:

0.0000744

AC:

EpiCase

AF:

0.0000548

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 13, 2021

The c.1599T>G (p.D533E) alteration is located in exon 15 (coding exon 15) of the FNBP1L gene. This alteration results from a T to G substitution at nucleotide position 1599, causing the aspartic acid (D) at amino acid position 533 to be replaced by a glutamic acid (E). 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

0.23

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.36

Cadd

Benign

Dann

Uncertain

0.99

DEOGEN2

Benign

0.030

T;.;.;.

Eigen

Benign

-0.18

Eigen_PC

Benign

-0.16

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.92

D;D;D;D

M_CAP

Benign

0.041

MetaRNN

Benign

0.11

T;T;T;T

MetaSVM

Benign

-0.85

MutationAssessor

Benign

1.6

L;.;.;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Pathogenic

0.79

PROVEAN

Benign

-1.6

N;N;.;.

REVEL

Uncertain

0.29

Sift

Benign

0.53

T;T;.;.

Sift4G

Benign

0.49

T;T;T;T

Polyphen

1.0, 0.24

.;D;.;B

Vest4

0.45

MutPred

0.31

Gain of disorder (P = 0.198);.;Gain of disorder (P = 0.198);.;

MVP

0.67

MPC

0.83

ClinPred

0.77

GERP RS

2.0

Varity_R

0.081

gMVP

0.29

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over