1-93536404-T-G

Position:

• chr1-93536404-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001164473.3(FNBP1L):​c.1063T>G​(p.Phe355Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000214 in 1,398,770 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: FNBP1L NM_001164473.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.86

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19443008).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FNBP1L	NM_001164473.3	c.1063T>G	p.Phe355Val	missense_variant	10/17	ENST00000271234.13	NP_001157945.1
FNBP1L	NM_001024948.3	c.990+1496T>G		intron_variant			NP_001020119.1
FNBP1L	NM_017737.5	c.990+1496T>G		intron_variant			NP_060207.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FNBP1L	ENST00000271234.13	c.1063T>G	p.Phe355Val	missense_variant	10/17	5	NM_001164473.3	ENSP00000271234.7
FNBP1L	ENST00000260506.12	c.990+1496T>G		intron_variant		1		ENSP00000260506.8
FNBP1L	ENST00000424449.2	c.598T>G	p.Phe200Val	missense_variant	5/12	2		ENSP00000397451.2
FNBP1L	ENST00000370253.6	c.990+1496T>G		intron_variant		5		ENSP00000359275.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000214 AC: 3 AN: 1398770 Hom.: 0 Cov.: 30 AF XY: 0.00000145 AC XY: 1 AN XY: 689884

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000278

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 02, 2023

The c.1063T>G (p.F355V) alteration is located in exon 10 (coding exon 10) of the FNBP1L gene. This alteration results from a T to G substitution at nucleotide position 1063, causing the phenylalanine (F) at amino acid position 355 to be replaced by a valine (V). 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	0.11
BayesDel_addAF	Benign	-0.031	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	19
DANN	Benign	0.96
DEOGEN2	Benign	0.057	T;.
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.13
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.76	T;T
M_CAP	Benign	0.043	D
MetaRNN	Benign	0.19	T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.5	L;.
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-0.89	N;.
REVEL	Benign	0.15
Sift	Benign	0.70	T;.
Sift4G	Benign	0.59	T;T
Vest4		0.44
MutPred		0.29		Loss of disorder (P = 0.2286);Loss of disorder (P = 0.2286);
MVP		0.66
MPC		0.58
ClinPred		0.18	T
GERP RS		2.7
Varity_R		0.084
gMVP		0.61

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: rs1671852314; hg19: chr1-94001961;