9-129902949-C-T

Variant names:

• chr9-129902949-C-T
• rs776554206
• NM_015033.3:c.1348G>A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_015033.3(FNBP1):​c.1348G>A​(p.Asp450Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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)
• Consequence: FNBP1 NM_015033.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.57

Genes affected

FNBP1 (HGNC:17069): (formin binding protein 1) The protein encoded by this gene is a member of the formin-binding-protein family. The protein contains an N-terminal Fer/Cdc42-interacting protein 4 (CIP4) homology (FCH) domain followed by a coiled-coil domain, a proline-rich motif, a second coiled-coil domain, a Rho family protein-binding domain (RBD), and a C-terminal SH3 domain. This protein binds sorting nexin 2 (SNX2), tankyrase (TNKS), and dynamin; an interaction between this protein and formin has not been demonstrated yet in human. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.801

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FNBP1	NM_015033.3	c.1348G>A	p.Asp450Asn	missense_variant	Exon 13 of 17	ENST00000446176.7	NP_055848.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FNBP1	ENST00000446176.7	c.1348G>A	p.Asp450Asn	missense_variant	Exon 13 of 17	1	NM_015033.3	ENSP00000413625.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000421 AC: 1 AN: 237770 Hom.: 0 AF XY: 0.00000776 AC XY: 1 AN XY: 128932

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: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000936

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ExAC AF: 0.00000828 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 06, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1348G>A (p.D450N) alteration is located in exon 13 (coding exon 13) of the FNBP1 gene. This alteration results from a G to A substitution at nucleotide position 1348, causing the aspartic acid (D) at amino acid position 450 to be replaced by an asparagine (N). 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	Benign	0.16
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.46
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.51	D;.;.;.
Eigen	Uncertain	0.61
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.97	D;D;D;D
M_CAP	Benign	0.035	D
MetaRNN	Pathogenic	0.80	D;D;D;D
MetaSVM	Benign	-0.85	T
MutationAssessor	Uncertain	2.2	M;.;.;.
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-4.6	D;.;.;D
REVEL	Benign	0.26
Sift	Benign	0.19	T;.;.;T
Sift4G	Pathogenic	0.0	D;T;D;T
Polyphen		0.93	P;D;.;P
Vest4		0.72
MutPred		0.51		Loss of helix (P = 0.1299);.;.;.;
MVP		0.80
MPC		0.59
ClinPred		0.99	D
GERP RS		5.8
Varity_R		0.46
gMVP		0.39

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

LitVar

Other links and lift over

dbSNP: rs776554206; hg19: chr9-132665228;