15-32774324-C-T

Position:

• chr15-32774324-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001277313.2(FMN1):​c.4246G>A​(p.Val1416Met) variant causes a missense change involving the alteration of a non-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)
• Consequence: FMN1 NM_001277313.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.32

Genes affected

FMN1 (HGNC:3768): (formin 1) This gene belongs to the formin homology family and encodes a protein that has a role in the formation of adherens junction and the polymerization of linear actin cables. The homologous gene in mouse is associated with limb deformity. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Sep 2015]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19747502).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FMN1	NM_001277313.2	c.4246G>A	p.Val1416Met	missense_variant	21/21	ENST00000616417.5	NP_001264242.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FMN1	ENST00000616417.5	c.4246G>A	p.Val1416Met	missense_variant	21/21	5	NM_001277313.2	ENSP00000479134	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 28

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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 03, 2022

The c.3577G>A (p.V1193M) alteration is located in exon 17 (coding exon 17) of the FMN1 gene. This alteration results from a G to A substitution at nucleotide position 3577, causing the valine (V) at amino acid position 1193 to be replaced by a methionine (M). 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	0.19
BayesDel_addAF	Benign	-0.043	T
BayesDel_noAF	Benign	-0.30
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.081	T;.;T;T
Eigen	Uncertain	0.22
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Benign	0.66	D
M_CAP	Benign	0.0074	T
MetaRNN	Benign	0.20	T;T;T;T
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	1.0	L;.;.;L
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-1.3	.;N;N;N
REVEL	Benign	0.11
Sift	Uncertain	0.0020	.;D;D;D
Sift4G	Uncertain	0.0070	D;D;D;D
Polyphen		0.77	.;P;.;.
Vest4		0.23
MutPred		0.13		.;Loss of phosphorylation at T1195 (P = 0.1136);.;.;
MVP		0.60
MPC		0.053
ClinPred		0.87	D
GERP RS		5.2
Varity_R		0.18
gMVP		0.28

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: rs2056344395; hg19: chr15-33066525;