11-47723005-C-T

Variant names:

• chr11-47723005-C-T
• rs923573810
• NM_015308.5:c.2776G>A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_015308.5(FNBP4):​c.2776G>A​(p.Glu926Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0000129 in 1,395,494 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: FNBP4 NM_015308.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.01

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.15664881).
• BS2: High AC in GnomAdExome4 at 18 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FNBP4	NM_015308.5	c.2776G>A	p.Glu926Lys	missense_variant	Exon 15 of 17	ENST00000263773.10	NP_056123.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FNBP4	ENST00000263773.10	c.2776G>A	p.Glu926Lys	missense_variant	Exon 15 of 17	1	NM_015308.5	ENSP00000263773.5
FNBP4	ENST00000530207.1	n.2894G>A		non_coding_transcript_exon_variant	Exon 3 of 3	2
FNBP4	ENST00000532646.6	n.890G>A		non_coding_transcript_exon_variant	Exon 3 of 3	2
FNBP4	ENST00000526109.6	n.229+1023G>A		intron_variant	Intron 2 of 3	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000193 AC: 3 AN: 155238 Hom.: 0 AF XY: 0.0000121 AC XY: 1 AN XY: 82756

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000455

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000317

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000129 AC: 18 AN: 1395494 Hom.: 0 Cov.: 32 AF XY: 0.00000870 AC XY: 6 AN XY: 689270

Gnomad4 AFR exome AF: 0.0000323

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000128

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000139

Gnomad4 OTH exome AF: 0.0000173

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 06, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2776G>A (p.E926K) alteration is located in exon 15 (coding exon 15) of the FNBP4 gene. This alteration results from a G to A substitution at nucleotide position 2776, causing the glutamic acid (E) at amino acid position 926 to be replaced by a lysine (K). 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	Uncertain	0.38
BayesDel_addAF	Benign	-0.087	T
BayesDel_noAF	Benign	-0.36
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0021	T
Eigen	Benign	0.0066
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.95	D
M_CAP	Benign	0.0075	T
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	L
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-0.66	N
REVEL	Benign	0.041
Sift	Benign	0.14	T
Sift4G	Benign	0.15	T
Polyphen		0.13	B
Vest4		0.44
MutPred		0.21		Gain of methylation at E926 (P = 4e-04);
MVP		0.25
MPC		0.38
ClinPred		0.27	T
GERP RS		5.3
Varity_R		0.084
gMVP		0.19

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: rs923573810; hg19: chr11-47744557; COSMIC: COSV55446698; COSMIC: COSV55446698;