Genetic Variant FNBP4:p.Ser772Ile (chr11-47724472-C-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_015308.5(FNBP4):c.2315G>T(p.Ser772Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00104 in 1,614,228 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S772N) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0053 ( 10 hom., cov: 32)

Exomes 𝑓: 0.00060 ( 8 hom. )

Consequence

FNBP4
NM_015308.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.0790

Publications

3 publications found

Variant links:

Genes affected

FNBP4 (HGNC:19752): (formin binding protein 4) This gene encodes a protein containing two tryptophan-rich WW domains that binds the proline-rich formin homology 1 domains of formin family proteins, suggesting a role in the regulation of cytoskeletal dynamics during cell division and migration. It also binds intersectin family proteins suggesting a role in the maintenance of membrane curvature at sites of nascent vesicle formation. Naturally occurring mutations in this gene are associated with Waardenburg anophthalmia syndrome. [provided by RefSeq, Apr 2017]

FNBP4 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0046437383).

BP6

Variant 11-47724472-C-A is Benign according to our data. Variant chr11-47724472-C-A is described in ClinVar as Benign. ClinVar VariationId is 776608.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00535 (815/152360) while in subpopulation AFR AF = 0.0176 (732/41584). AF 95% confidence interval is 0.0165. There are 10 homozygotes in GnomAd4. There are 367 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 815 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015308.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FNBP4	NM_015308.5	MANE Select	c.2315G>T	p.Ser772Ile	missense	Exon 13 of 17	NP_056123.2	Q8N3X1-1
FNBP4	NM_001441100.1		c.2540G>T	p.Ser847Ile	missense	Exon 14 of 18	NP_001428029.1
FNBP4	NM_001441101.1		c.2540G>T	p.Ser847Ile	missense	Exon 14 of 18	NP_001428030.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FNBP4	ENST00000263773.10	TSL:1 MANE Select	c.2315G>T	p.Ser772Ile	missense	Exon 13 of 17	ENSP00000263773.5	Q8N3X1-1
FNBP4	ENST00000917808.1		c.2534G>T	p.Ser845Ile	missense	Exon 14 of 18	ENSP00000587867.1
FNBP4	ENST00000883715.1		c.2321G>T	p.Ser774Ile	missense	Exon 13 of 17	ENSP00000553774.1

Frequencies

GnomAD3 genomes

AF:

0.00536

AC:

816

AN:

152242

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0177

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00425

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.00478

GnomAD2 exomes

AF:

0.00148

AC:

366

AN:

247014

AF XY:

0.00110

show subpopulations

Gnomad AFR exome

AF:

0.0195

Gnomad AMR exome

AF:

0.00133

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000993

Gnomad OTH exome

AF:

0.000993

GnomAD4 exome

AF:

0.000595

AC:

870

AN:

1461868

Hom.:

Cov.:

AF XY:

0.000558

AC XY:

406

AN XY:

727232

show subpopulations

African (AFR)

AF:

0.0185

AC:

619

AN:

33480

American (AMR)

AF:

0.00127

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000696

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00139

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000782

AC:

AN:

1111994

Other (OTH)

AF:

0.00154

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

148

198

247

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00535

AC:

815

AN:

152360

Hom.:

Cov.:

AF XY:

0.00492

AC XY:

367

AN XY:

74518

show subpopulations

African (AFR)

AF:

0.0176

AC:

732

AN:

41584

American (AMR)

AF:

0.00425

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000103

AC:

AN:

68042

Other (OTH)

AF:

0.00473

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

121

161

201

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00177

Hom.:

Bravo

AF:

0.00675

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.0189

AC:

ESP6500EA

AF:

0.000243

AC:

ExAC

AF:

0.00164

AC:

198

Asia WGS

AF:

0.00202

AC:

AN:

3478

EpiCase

AF:

0.000218

EpiControl

AF:

0.000119

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.53

CADD

Benign

(source)

DANN

Benign

0.92

DEOGEN2

Benign

0.0043

Eigen

Benign

-0.84

Eigen_PC

Benign

-0.84

FATHMM_MKL

Uncertain

0.83

MetaRNN

Benign

0.0046

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.5

PhyloP100

0.079

PrimateAI

Benign

0.38

PROVEAN

Benign

-1.9

REVEL

Benign

0.078

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.025

Polyphen

0.28

Vest4

0.42

MVP

0.16

MPC

0.30

ClinPred

0.034

GERP RS

-3.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.11

gMVP

0.28

Mutation Taster

=91/9

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over