1-93534786-A-T

Variant names:

• chr1-93534786-A-T
• rs769520098
• NM_001164473.3:c.868A>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001164473.3(FNBP1L):​c.868A>T​(p.Ile290Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000705 in 1,418,738 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I290V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: FNBP1L NM_001164473.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.66
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15368113).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001164473.3. 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
	FNBP1L	NM_001164473.3	MANE Select	c.868A>T	p.Ile290Leu	missense	Exon 9 of 17	NP_001157945.1	Q5T0N5-1
	FNBP1L	NM_001024948.3		c.868A>T	p.Ile290Leu	missense	Exon 9 of 14	NP_001020119.1	Q5T0N5-4
	FNBP1L	NM_017737.5		c.868A>T	p.Ile290Leu	missense	Exon 9 of 15	NP_060207.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FNBP1L	ENST00000271234.13	TSL:5 MANE Select	c.868A>T	p.Ile290Leu	missense	Exon 9 of 17	ENSP00000271234.7	Q5T0N5-1
	FNBP1L	ENST00000260506.12	TSL:1	c.868A>T	p.Ile290Leu	missense	Exon 9 of 14	ENSP00000260506.8	Q5T0N5-4
	FNBP1L	ENST00000868905.1		c.868A>T	p.Ile290Leu	missense	Exon 9 of 16	ENSP00000538964.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.05e-7 AC: 1 AN: 1418738 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 701430

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32542

American (AMR) AF: 0.00 AC: 0 AN: 38594

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25466

East Asian (EAS) AF: 0.00 AC: 0 AN: 37924

South Asian (SAS) AF: 0.00 AC: 0 AN: 80604

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50850

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5714

European-Non Finnish (NFE) AF: 9.19e-7 AC: 1 AN: 1088232

Other (OTH) AF: 0.00 AC: 0 AN: 58812

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	21
DANN	Benign	0.96
DEOGEN2	Benign	0.041	T
Eigen	Benign	-0.14
Eigen_PC	Benign	0.061
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.0076	T
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		4.7
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-0.10	N
REVEL	Benign	0.063
Sift	Benign	0.32	T
Sift4G	Benign	0.68	T
Polyphen		0.0040	B
Vest4		0.25
MutPred		0.39		Loss of catalytic residue at I290 (P = 0.0479)
MVP		0.24
MPC		0.36
ClinPred		0.63	D
GERP RS		5.4
Varity_R		0.12
gMVP		0.37
Mutation Taster		=69/31	polymorphism

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: rs769520098; hg19: chr1-94000343;