1-93529745-G-T

Variant names:

• chr1-93529745-G-T
• NM_001164473.3:c.499G>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP3 BP4

The NM_001164473.3(FNBP1L):​c.499G>T​(p.Asp167Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: FNBP1L NM_001164473.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.57

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Multiple lines of computational evidence support a deleterious effect 7: AlphaMissense, BayesDel_addAF, Cadd, Eigen, phyloP100way_vertebrate, PrimateAI, PROVEAN [when max_spliceai, M_CAP, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.3984822).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FNBP1L	NM_001164473.3	c.499G>T	p.Asp167Tyr	missense_variant	Exon 6 of 17	ENST00000271234.13	NP_001157945.1
FNBP1L	NM_001024948.3	c.499G>T	p.Asp167Tyr	missense_variant	Exon 6 of 14		NP_001020119.1
FNBP1L	NM_017737.5	c.499G>T	p.Asp167Tyr	missense_variant	Exon 6 of 15		NP_060207.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FNBP1L	ENST00000271234.13	c.499G>T	p.Asp167Tyr	missense_variant	Exon 6 of 17	5	NM_001164473.3	ENSP00000271234.7
FNBP1L	ENST00000260506.12	c.499G>T	p.Asp167Tyr	missense_variant	Exon 6 of 14	1		ENSP00000260506.8
FNBP1L	ENST00000370253.6	c.499G>T	p.Asp167Tyr	missense_variant	Exon 6 of 15	5		ENSP00000359275.2
FNBP1L	ENST00000424449.2	c.34G>T	p.Asp12Tyr	missense_variant	Exon 1 of 12	2		ENSP00000397451.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1361088 Hom.: 0 Cov.: 27 AF XY: 0.00 AC XY: 0 AN XY: 671006

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 08, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.499G>T (p.D167Y) alteration is located in exon 6 (coding exon 6) of the FNBP1L gene. This alteration results from a G to T substitution at nucleotide position 499, causing the aspartic acid (D) at amino acid position 167 to be replaced by a tyrosine (Y). 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	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.070
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Benign	0.37	T;.;.;.
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.92
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D;D
M_CAP	Benign	0.040	D
MetaRNN	Benign	0.40	T;T;T;T
MetaSVM	Benign	-0.54	T
MutationAssessor	Uncertain	2.5	M;M;.;M
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-7.4	D;D;.;D
REVEL	Uncertain	0.44
Sift	Pathogenic	0.0	D;D;.;D
Sift4G	Pathogenic	0.0010	D;D;D;D
Polyphen		1.0, 1.0	.;D;.;D
Vest4		0.45
MutPred		0.38		Loss of ubiquitination at K172 (P = 0.0183);Loss of ubiquitination at K172 (P = 0.0183);Loss of ubiquitination at K172 (P = 0.0183);Loss of ubiquitination at K172 (P = 0.0183);
MVP		0.71
MPC		1.2
ClinPred		0.99	D
GERP RS		5.7
Varity_R		0.92
gMVP		0.55

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-93995302;