17-45241536-G-T

Variant names:

• chr17-45241536-G-T
• NM_005892.4:c.1487G>T

Variant summary

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

The NM_005892.4(FMNL1):​c.1487G>T​(p.Gly496Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000014 in 1,424,900 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 0.0000014 (0 hom.)
• Consequence: FMNL1 NM_005892.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.28

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 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=0.31808275).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FMNL1	NM_005892.4	c.1487G>T	p.Gly496Val	missense_variant	Exon 14 of 27	ENST00000331495.8	NP_005883.3
FMNL1	NM_001411128.1	c.1487G>T	p.Gly496Val	missense_variant	Exon 14 of 26		NP_001398057.1
FMNL1-AS1	NR_186807.1	n.235C>A		non_coding_transcript_exon_variant	Exon 1 of 2
FMNL1-AS1	NR_186808.1	n.235C>A		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.1487G>T	p.Gly496Val	missense_variant	Exon 14 of 27	1	NM_005892.4	ENSP00000329219.2
FMNL1	ENST00000587489.6	c.1487G>T	p.Gly496Val	missense_variant	Exon 14 of 26	1		ENSP00000465474.2
FMNL1-AS1	ENST00000587534.1	n.199C>A		non_coding_transcript_exon_variant	Exon 1 of 2	2
FMNL1	ENST00000587856.1	n.1844G>T		non_coding_transcript_exon_variant	Exon 7 of 16	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000140 AC: 2 AN: 1424900 Hom.: 0 Cov.: 35 AF XY: 0.00000283 AC XY: 2 AN XY: 705702

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: 0.0000122

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.14e-7

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

Jul 13, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1487G>T (p.G496V) alteration is located in exon 14 (coding exon 14) of the FMNL1 gene. This alteration results from a G to T substitution at nucleotide position 1487, causing the glycine (G) at amino acid position 496 to be replaced by a valine (V). 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	0.24
BayesDel_addAF	Uncertain	0.039	T
BayesDel_noAF	Benign	-0.18
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.22	T;T;.
Eigen	Uncertain	0.26
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.79	T;D;T
M_CAP	Pathogenic	0.32	D
MetaRNN	Benign	0.32	T;T;T
MetaSVM	Benign	-0.34	T
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-3.7	D;.;.
REVEL	Uncertain	0.41
Sift	Uncertain	0.0040	D;.;.
Sift4G	Uncertain	0.040	D;T;D
Polyphen		0.98	D;.;.
Vest4		0.30
MutPred		0.27		Loss of catalytic residue at G496 (P = 0.0094);.;.;
MVP		0.64
MPC		0.73
ClinPred		0.97	D
GERP RS		4.3
Varity_R		0.33
gMVP		0.35

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: chr17-43318903;