11-47719983-C-T

Variant names:

• chr11-47719983-C-T
• rs769984885
• NM_015308.5:c.2909G>A

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 3P and 4B. PM2 PP3 BS2

The NM_015308.5(FNBP4):​c.2909G>A​(p.Arg970Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,780 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: FNBP4 NM_015308.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.53
• 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]

ENSG00000305470 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.746
• BS2: High AC in GnomAdExome4 at 5 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FNBP4	NM_015308.5	MANE Select	c.2909G>A	p.Arg970Gln	missense	Exon 16 of 17	NP_056123.2	Q8N3X1-1
	FNBP4	NM_001441100.1		c.3134G>A	p.Arg1045Gln	missense	Exon 17 of 18	NP_001428029.1
	FNBP4	NM_001441101.1		c.3134G>A	p.Arg1045Gln	missense	Exon 17 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.2909G>A	p.Arg970Gln	missense	Exon 16 of 17	ENSP00000263773.5	Q8N3X1-1
	FNBP4	ENST00000917808.1		c.3128G>A	p.Arg1043Gln	missense	Exon 17 of 18	ENSP00000587867.1
	FNBP4	ENST00000883715.1		c.2915G>A	p.Arg972Gln	missense	Exon 16 of 17	ENSP00000553774.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000160 AC: 4 AN: 249424 AF XY: 0.00000739

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000869

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000556

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461780 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 727196

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.0000671 AC: 3 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111940

Other (OTH) AF: 0.00 AC: 0 AN: 60390

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Uncertain	0.059	T
BayesDel_noAF	Uncertain	0.040
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.042	T
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Benign	0.056	D
MetaRNN	Pathogenic	0.75	D
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	2.0	M
PhyloP100		7.5
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.28
Sift	Uncertain	0.011	D
Sift4G	Uncertain	0.013	D
Polyphen		0.99	D
Vest4		0.76
MutPred		0.11		Gain of glycosylation at S972 (P = 0.086)
MVP		0.76
MPC		2.5
ClinPred		0.98	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.28
gMVP		0.29
Mutation Taster		=83/17	polymorphism

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

Other links and lift over

dbSNP: rs769984885; hg19: chr11-47741535;