1-93524302-G-C

Position:

• chr1-93524302-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001164473.3(FNBP1L):​c.384G>C​(p.Met128Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000221 in 1,358,860 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000022 (0 hom.)
• Consequence: FNBP1L NM_001164473.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.55

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2667278).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FNBP1L	NM_001164473.3	c.384G>C	p.Met128Ile	missense_variant	5/17	ENST00000271234.13	NP_001157945.1
FNBP1L	NM_001024948.3	c.384G>C	p.Met128Ile	missense_variant	5/14		NP_001020119.1
FNBP1L	NM_017737.5	c.384G>C	p.Met128Ile	missense_variant	5/15		NP_060207.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FNBP1L	ENST00000271234.13	c.384G>C	p.Met128Ile	missense_variant	5/17	5	NM_001164473.3	ENSP00000271234.7
FNBP1L	ENST00000260506.12	c.384G>C	p.Met128Ile	missense_variant	5/14	1		ENSP00000260506.8
FNBP1L	ENST00000370253.6	c.384G>C	p.Met128Ile	missense_variant	5/15	5		ENSP00000359275.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000221 AC: 3 AN: 1358860 Hom.: 0 Cov.: 30 AF XY: 0.00000149 AC XY: 1 AN XY: 669380

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: 0.00000283

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

Sep 26, 2024

The c.384G>C (p.M128I) alteration is located in exon 5 (coding exon 5) of the FNBP1L gene. This alteration results from a G to C substitution at nucleotide position 384, causing the methionine (M) at amino acid position 128 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	Uncertain	0.41
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.049	T;.;.;.
Eigen	Benign	0.17
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.86	D;D;D;D
M_CAP	Benign	0.0072	T
MetaRNN	Benign	0.27	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	N;N;.;N
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-0.97	N;N;.;N
REVEL	Benign	0.12
Sift	Benign	0.049	D;D;.;D
Sift4G	Uncertain	0.051	T;T;T;T
Polyphen		0.77, 0.0080	.;P;.;B
Vest4		0.40
MutPred		0.48		Loss of catalytic residue at M128 (P = 0.0082);Loss of catalytic residue at M128 (P = 0.0082);Loss of catalytic residue at M128 (P = 0.0082);Loss of catalytic residue at M128 (P = 0.0082);
MVP		0.33
MPC		0.41
ClinPred		0.53	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.31
gMVP		0.17

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: rs780845896; hg19: chr1-93989859;