11-47724144-G-C

Position:

• chr11-47724144-G-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_015308.5(FNBP4):​c.2348C>G​(p.Ser783Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0063 in 1,614,130 control chromosomes in the GnomAD database, including 175 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0080 (37 hom., cov: 32)
  • Exomes 𝑓: 0.0061 (138 hom.)
• Consequence: FNBP4 NM_015308.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 5.55

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0028734803).
• BP6: Variant 11-47724144-G-C is Benign according to our data. Variant chr11-47724144-G-C is described in ClinVar as [Benign]. Clinvar id is 784520.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 1225 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FNBP4	NM_015308.5	c.2348C>G	p.Ser783Cys	missense_variant	14/17	ENST00000263773.10	NP_056123.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FNBP4	ENST00000263773.10	c.2348C>G	p.Ser783Cys	missense_variant	14/17	1	NM_015308.5	ENSP00000263773	P1
FNBP4	ENST00000526109.6	n.113C>G		non_coding_transcript_exon_variant	2/4	3
FNBP4	ENST00000530207.1	n.2466C>G		non_coding_transcript_exon_variant	2/3	2
FNBP4	ENST00000532646.6	n.462C>G		non_coding_transcript_exon_variant	2/3	2

Frequencies

GnomAD3 genomes AF: 0.00805 AC: 1226 AN: 152224 Hom.: 37 Cov.: 32

Gnomad AFR AF: 0.000796

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00124

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000620

Gnomad FIN AF: 0.0772

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00491

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00962 AC: 2400 AN: 249448 Hom.: 53 AF XY: 0.00950 AC XY: 1286 AN XY: 135344

Gnomad AFR exome AF: 0.000452

Gnomad AMR exome AF: 0.000928

Gnomad ASJ exome AF: 0.00308

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000752

Gnomad FIN exome AF: 0.0722

Gnomad NFE exome AF: 0.00621

Gnomad OTH exome AF: 0.00809

GnomAD4 exome AF: 0.00612 AC: 8940 AN: 1461788 Hom.: 138 Cov.: 32 AF XY: 0.00605 AC XY: 4400 AN XY: 727188

Gnomad4 AFR exome AF: 0.000478

Gnomad4 AMR exome AF: 0.000962

Gnomad4 ASJ exome AF: 0.00249

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00126

Gnomad4 FIN exome AF: 0.0650

Gnomad4 NFE exome AF: 0.00441

Gnomad4 OTH exome AF: 0.00530

GnomAD4 genome AF: 0.00804 AC: 1225 AN: 152342 Hom.: 37 Cov.: 32 AF XY: 0.0110 AC XY: 816 AN XY: 74494

Gnomad4 AFR AF: 0.000793

Gnomad4 AMR AF: 0.00124

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.0772

Gnomad4 NFE AF: 0.00491

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00479 Hom.: 4

Bravo AF: 0.00272

TwinsUK AF: 0.00324 AC: 12

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.000802 AC: 3

ESP6500EA AF: 0.00426 AC: 35

ExAC AF: 0.00834 AC: 1008

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 16, 2019	This variant is associated with the following publications: (PMID: 30653986) -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 15, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0058	T
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.95	D
MetaRNN	Benign	0.0029	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.5	L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.096
Sift	Benign	0.093	T
Sift4G	Uncertain	0.046	D
Polyphen		0.89	P
Vest4		0.39
MVP		0.38
MPC		0.50
ClinPred		0.025	T
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.079
gMVP		0.12

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: rs138653244; hg19: chr11-47745696;