1-93532994-C-T

Variant names:

• chr1-93532994-C-T
• rs370837605
• NM_001164473.3:c.712C>T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP3_Moderate BS2

The NM_001164473.3(FNBP1L):​c.712C>T​(p.Arg238Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000044 in 1,613,026 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000045 (0 hom.)
• Consequence: FNBP1L NM_001164473.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.54

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 Likely_benign. Variant got -2 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.843
• BS2: High AC in GnomAd4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FNBP1L	NM_001164473.3	c.712C>T	p.Arg238Cys	missense_variant	Exon 8 of 17	ENST00000271234.13	NP_001157945.1
FNBP1L	NM_001024948.3	c.712C>T	p.Arg238Cys	missense_variant	Exon 8 of 14		NP_001020119.1
FNBP1L	NM_017737.5	c.712C>T	p.Arg238Cys	missense_variant	Exon 8 of 15		NP_060207.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FNBP1L	ENST00000271234.13	c.712C>T	p.Arg238Cys	missense_variant	Exon 8 of 17	5	NM_001164473.3	ENSP00000271234.7
FNBP1L	ENST00000260506.12	c.712C>T	p.Arg238Cys	missense_variant	Exon 8 of 14	1		ENSP00000260506.8
FNBP1L	ENST00000370253.6	c.712C>T	p.Arg238Cys	missense_variant	Exon 8 of 15	5		ENSP00000359275.2
FNBP1L	ENST00000424449.2	c.247C>T	p.Arg83Cys	missense_variant	Exon 3 of 12	2		ENSP00000397451.2

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152080 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000120 AC: 3 AN: 248984 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135080

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: 0.0000266

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000452 AC: 66 AN: 1460946 Hom.: 0 Cov.: 30 AF XY: 0.0000413 AC XY: 30 AN XY: 726742

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000549

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152080 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74282

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.0000658 Hom.: 0

Bravo AF: 0.0000567

ESP6500AA AF: 0.000270 AC: 1

ESP6500EA AF: 0.000122 AC: 1

ExAC AF: 0.00000828 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 28, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.712C>T (p.R238C) alteration is located in exon 8 (coding exon 8) of the FNBP1L gene. This alteration results from a C to T substitution at nucleotide position 712, causing the arginine (R) at amino acid position 238 to be replaced by a cysteine (C). 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	0.33
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.10
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.40	T;.;.;.
Eigen	Uncertain	0.68
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.99	D;D;D;D
M_CAP	Benign	0.027	D
MetaRNN	Pathogenic	0.84	D;D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.4	M;M;.;M
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-5.1	D;D;.;D
REVEL	Uncertain	0.39
Sift	Uncertain	0.0010	D;D;.;D
Sift4G	Uncertain	0.0040	D;D;D;D
Polyphen		1.0, 0.94	.;D;.;P
Vest4		0.91
MVP		0.81
MPC		1.3
ClinPred		0.98	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.60
gMVP		0.86

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs370837605; hg19: chr1-93998551;