9-129900442-C-T

Variant names:

• chr9-129900442-C-T
• rs200153012
• NM_015033.3:c.1534G>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4 BS2

The NM_015033.3(FNBP1):​c.1534G>A​(p.Ala512Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000113 in 1,598,754 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A512P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: FNBP1 NM_015033.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.92
• Publications: 4 publications found

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

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.27957192).
• BS2: High AC in GnomAd4 at 9 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015033.3. 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
	FNBP1	NM_015033.3	MANE Select	c.1534G>A	p.Ala512Thr	missense	Exon 14 of 17	NP_055848.1	Q96RU3-1
	FNBP1	NM_001438006.1		c.1618G>A	p.Ala540Thr	missense	Exon 15 of 18	NP_001424935.1	A0A8V8TQ35
	FNBP1	NM_001439039.1		c.1603G>A	p.Ala535Thr	missense	Exon 14 of 16	NP_001425968.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FNBP1	ENST00000446176.7	TSL:1 MANE Select	c.1534G>A	p.Ala512Thr	missense	Exon 14 of 17	ENSP00000413625.1	Q96RU3-1
	FNBP1	ENST00000699492.1		c.1618G>A	p.Ala540Thr	missense	Exon 15 of 18	ENSP00000514403.1	A0A8V8TQ35
	FNBP1	ENST00000703559.1		c.1534G>A	p.Ala512Thr	missense	Exon 14 of 16	ENSP00000515375.1	A0A994J3V8

Frequencies

GnomAD3 genomes AF: 0.0000591 AC: 9 AN: 152236 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000128 AC: 3 AN: 233824 AF XY: 0.00000785

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000970

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000622 AC: 9 AN: 1446400 Hom.: 0 Cov.: 30 AF XY: 0.00000278 AC XY: 2 AN XY: 719382

African (AFR) AF: 0.00 AC: 0 AN: 32646

American (AMR) AF: 0.0000718 AC: 3 AN: 41796

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25604

East Asian (EAS) AF: 0.0000259 AC: 1 AN: 38550

South Asian (SAS) AF: 0.0000119 AC: 1 AN: 83876

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53092

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5692

European-Non Finnish (NFE) AF: 0.00000362 AC: 4 AN: 1105414

Other (OTH) AF: 0.00 AC: 0 AN: 59730

GnomAD4 genome AF: 0.0000591 AC: 9 AN: 152354 Hom.: 0 Cov.: 31 AF XY: 0.0000940 AC XY: 7 AN XY: 74504

African (AFR) AF: 0.00 AC: 0 AN: 41586

American (AMR) AF: 0.000457 AC: 7 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.0000107 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.0000165 AC: 2

Asia WGS AF: 0.000289 AC: 1 AN: 3478

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	0.083
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.28
CADD	Uncertain	24
DANN	Benign	0.92
DEOGEN2	Benign	0.088	T
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.17
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.87	D
M_CAP	Uncertain	0.099	D
MetaRNN	Benign	0.28	T
MetaSVM	Benign	-0.57	T
MutationAssessor	Benign	2.0	M
PhyloP100		4.9
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-0.75	N
REVEL	Benign	0.16
Sift	Benign	0.48	T
Sift4G	Benign	0.14	T
Polyphen		0.50	P
Vest4		0.48
MutPred		0.16		Gain of glycosylation at A512 (P = 0.0291)
MVP		0.71
MPC		0.44
ClinPred		0.77	D
GERP RS		4.2
Varity_R		0.064
gMVP		0.44
Mutation Taster		=47/53	disease causing

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: rs200153012; hg19: chr9-132662721; COSMIC: COSV100852851;