1-93530860-G-A

Variant names:

• chr1-93530860-G-A
• rs546429949
• NM_001164473.3:c.616G>A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001164473.3(FNBP1L):​c.616G>A​(p.Val206Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000117 in 1,544,664 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: FNBP1L NM_001164473.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.62

Genes affected

FNBP1L (HGNC:20851): (formin binding protein 1 like) The protein encoded by this gene binds to both CDC42 and N-WASP. This protein promotes CDC42-induced actin polymerization by activating the N-WASP-WIP complex and, therefore, is involved in a pathway that links cell surface signals to the actin cytoskeleton. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.06559414).
• BS2: High AC in GnomAdExome4 at 16 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FNBP1L	NM_001164473.3	c.616G>A	p.Val206Ile	missense_variant	Exon 7 of 17	ENST00000271234.13	NP_001157945.1
FNBP1L	NM_001024948.3	c.616G>A	p.Val206Ile	missense_variant	Exon 7 of 14		NP_001020119.1
FNBP1L	NM_017737.5	c.616G>A	p.Val206Ile	missense_variant	Exon 7 of 15		NP_060207.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FNBP1L	ENST00000271234.13	c.616G>A	p.Val206Ile	missense_variant	Exon 7 of 17	5	NM_001164473.3	ENSP00000271234.7
FNBP1L	ENST00000260506.12	c.616G>A	p.Val206Ile	missense_variant	Exon 7 of 14	1		ENSP00000260506.8
FNBP1L	ENST00000370253.6	c.616G>A	p.Val206Ile	missense_variant	Exon 7 of 15	5		ENSP00000359275.2
FNBP1L	ENST00000424449.2	c.151G>A	p.Val51Ile	missense_variant	Exon 2 of 12	2		ENSP00000397451.2

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152144 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000191 AC: 3 AN: 156930 Hom.: 0 AF XY: 0.0000242 AC XY: 2 AN XY: 82526

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: 0.0000322

Gnomad OTH exome AF: 0.000227

GnomAD4 exome AF: 0.0000115 AC: 16 AN: 1392402 Hom.: 0 Cov.: 28 AF XY: 0.0000146 AC XY: 10 AN XY: 687124

Gnomad4 AFR exome AF: 0.00

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: 0.0000121

Gnomad4 OTH exome AF: 0.0000346

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152262 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74450

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000450 Hom.: 0

Bravo AF: 0.0000227

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 14, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.616G>A (p.V206I) alteration is located in exon 7 (coding exon 7) of the FNBP1L gene. This alteration results from a G to A substitution at nucleotide position 616, causing the valine (V) at amino acid position 206 to be replaced by an isoleucine (I). 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	0.065
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	15
DANN	Uncertain	0.98
DEOGEN2	Benign	0.052	T;.;.;.
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.33
FATHMM_MKL	Benign	0.60	D
LIST_S2	Benign	0.82	T;T;T;T
M_CAP	Benign	0.0026	T
MetaRNN	Benign	0.066	T;T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	-1.1	N;N;.;N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.61	N;N;.;N
REVEL	Benign	0.031
Sift	Benign	0.24	T;T;.;T
Sift4G	Benign	0.20	T;T;T;T
Polyphen		0.0	.;B;.;B
Vest4		0.11
MutPred		0.40		Gain of catalytic residue at V207 (P = 0.1291);Gain of catalytic residue at V207 (P = 0.1291);Gain of catalytic residue at V207 (P = 0.1291);Gain of catalytic residue at V207 (P = 0.1291);
MVP		0.20
MPC		0.30
ClinPred		0.17	T
GERP RS		2.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.024
gMVP		0.11

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: rs546429949; hg19: chr1-93996417;