11-47724613-G-T

Variant names:

• chr11-47724613-G-T
• rs2097559066
• NM_015308.5:c.2174C>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_015308.5(FNBP4):​c.2174C>A​(p.Pro725His) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P725L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FNBP4 NM_015308.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.28
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3288623).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FNBP4	NM_015308.5	MANE Select	c.2174C>A	p.Pro725His	missense	Exon 13 of 17	NP_056123.2	Q8N3X1-1
	FNBP4	NM_001441100.1		c.2399C>A	p.Pro800His	missense	Exon 14 of 18	NP_001428029.1
	FNBP4	NM_001441101.1		c.2399C>A	p.Pro800His	missense	Exon 14 of 18	NP_001428030.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FNBP4	ENST00000263773.10	TSL:1 MANE Select	c.2174C>A	p.Pro725His	missense	Exon 13 of 17	ENSP00000263773.5	Q8N3X1-1
	FNBP4	ENST00000917808.1		c.2393C>A	p.Pro798His	missense	Exon 14 of 18	ENSP00000587867.1
	FNBP4	ENST00000883715.1		c.2180C>A	p.Pro727His	missense	Exon 13 of 17	ENSP00000553774.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.65
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Benign	0.049	T
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Pathogenic	1.0	D
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.33	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L
PhyloP100		6.3
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-3.4	D
REVEL	Benign	0.17
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.48
MutPred		0.28		Loss of glycosylation at P725 (P = 5e-04)
MVP		0.26
MPC		0.74
ClinPred		0.97	D
GERP RS		3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.30
gMVP		0.30
Mutation Taster		=89/11	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs2097559066; hg19: chr11-47746165;