chr9-129895909-C-T

Variant names:

• chr9-129895909-C-T
• rs374562503
• NM_015033.3:c.1775G>A

Variant summary

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

The NM_015033.3(FNBP1):​c.1775G>A​(p.Arg592Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000105 in 1,613,612 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: 𝑓 0.0000066 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: FNBP1 NM_015033.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.57
• Publications: 5 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 -3 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.819
• BS2: High AC in GnomAdExome4 at 16 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.1775G>A	p.Arg592Gln	missense	Exon 16 of 17	NP_055848.1	Q96RU3-1
	FNBP1	NM_001438006.1		c.1859G>A	p.Arg620Gln	missense	Exon 17 of 18	NP_001424935.1	A0A8V8TQ35
	FNBP1	NM_001439039.1		c.1844G>A	p.Arg615Gln	missense	Exon 16 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.1775G>A	p.Arg592Gln	missense	Exon 16 of 17	ENSP00000413625.1	Q96RU3-1
	FNBP1	ENST00000699492.1		c.1859G>A	p.Arg620Gln	missense	Exon 17 of 18	ENSP00000514403.1	A0A8V8TQ35
	FNBP1	ENST00000703559.1		c.1778G>A	p.Arg593Gln	missense	Exon 16 of 16	ENSP00000515375.1	A0A994J3V8

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152026 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000201 AC: 5 AN: 249056 AF XY: 0.0000148

Gnomad AFR exome AF: 0.0000646

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000266

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000109 AC: 16 AN: 1461586 Hom.: 0 Cov.: 34 AF XY: 0.00000688 AC XY: 5 AN XY: 727086

African (AFR) AF: 0.0000597 AC: 2 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86232

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53368

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

European-Non Finnish (NFE) AF: 0.00000989 AC: 11 AN: 1111838

Other (OTH) AF: 0.0000331 AC: 2 AN: 60372

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152026 Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1 AN XY: 74260

African (AFR) AF: 0.0000242 AC: 1 AN: 41362

American (AMR) AF: 0.00 AC: 0 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10596

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68008

Other (OTH) AF: 0.00 AC: 0 AN: 2078

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000121 AC: 1

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	0.25
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	0.11
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.26	T
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.055	D
MetaRNN	Pathogenic	0.82	D
MetaSVM	Benign	-0.58	T
MutationAssessor	Benign	1.8	L
PhyloP100		7.6
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-2.7	D
REVEL	Uncertain	0.38
Sift	Benign	0.056	T
Sift4G	Benign	0.11	T
Polyphen		1.0	D
Vest4		0.92
MVP		0.76
MPC		0.84
ClinPred		0.89	D
GERP RS		5.1
Varity_R		0.37
gMVP		0.73
Mutation Taster		=23/77	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: rs374562503; hg19: chr9-132658188; COSMIC: COSV63085811; COSMIC: COSV63085811;