17-45241544-G-C

Variant names:

• chr17-45241544-G-C
• rs1033052094
• NM_005892.4:c.1495G>C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Moderate BS2

The NM_005892.4(FMNL1):​c.1495G>C​(p.Val499Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000352 in 1,422,364 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 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: 0.0000035 (0 hom.)
• Consequence: FMNL1 NM_005892.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.979

Genes affected

FMNL1 (HGNC:1212): (formin like 1) This gene encodes a formin-related protein. Formin-related proteins have been implicated in morphogenesis, cytokinesis, and cell polarity. An alternative splice variant has been described but its full length sequence has not been determined. [provided by RefSeq, Jul 2008]

FMNL1-AS1 (HGNC:55717): (FMNL1 antisense RNA 1)

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07976547).
• BS2: High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FMNL1	NM_005892.4	c.1495G>C	p.Val499Leu	missense_variant	Exon 14 of 27	ENST00000331495.8	NP_005883.3
FMNL1	NM_001411128.1	c.1495G>C	p.Val499Leu	missense_variant	Exon 14 of 26		NP_001398057.1
FMNL1-AS1	NR_186807.1	n.227C>G		non_coding_transcript_exon_variant	Exon 1 of 2
FMNL1-AS1	NR_186808.1	n.227C>G		non_coding_transcript_exon_variant	Exon 1 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FMNL1	ENST00000331495.8	c.1495G>C	p.Val499Leu	missense_variant	Exon 14 of 27	1	NM_005892.4	ENSP00000329219.2
FMNL1	ENST00000587489.6	c.1495G>C	p.Val499Leu	missense_variant	Exon 14 of 26	1		ENSP00000465474.2
FMNL1-AS1	ENST00000587534.1	n.191C>G		non_coding_transcript_exon_variant	Exon 1 of 2	2
FMNL1	ENST00000587856.1	n.1852G>C		non_coding_transcript_exon_variant	Exon 7 of 16	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000556 AC: 1 AN: 180018 Hom.: 0 AF XY: 0.0000102 AC XY: 1 AN XY: 97884

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: 0.00

Gnomad OTH exome AF: 0.000210

GnomAD4 exome AF: 0.00000352 AC: 5 AN: 1422364 Hom.: 0 Cov.: 35 AF XY: 0.00000568 AC XY: 4 AN XY: 704210

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000789

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000274

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 13, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1495G>C (p.V499L) alteration is located in exon 14 (coding exon 14) of the FMNL1 gene. This alteration results from a G to C substitution at nucleotide position 1495, causing the valine (V) at amino acid position 499 to be replaced by a leucine (L). 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	0.21
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	17
DANN	Benign	0.86
DEOGEN2	Benign	0.020	T;T;.
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.56
FATHMM_MKL	Benign	0.48	N
LIST_S2	Benign	0.76	T;D;T
M_CAP	Uncertain	0.098	D
MetaRNN	Benign	0.080	T;T;T
MetaSVM	Benign	-0.94	T
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-0.59	N;.;.
REVEL	Benign	0.069
Sift	Benign	0.74	T;.;.
Sift4G	Benign	1.0	T;T;T
Polyphen		0.0070	B;.;.
Vest4		0.24
MutPred		0.29		Loss of sheet (P = 0.0817);.;.;
MVP		0.44
MPC		0.57
ClinPred		0.097	T
GERP RS		1.9
Varity_R		0.034
gMVP		0.12

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: rs1033052094; hg19: chr17-43318911;