1-240092805-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_020066.5(FMN2):c.696T>C(p.Pro232=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00457 in 1,585,654 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0039 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0046 (23 hom.)
• Consequence: FMN2 NM_020066.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.00300

Genes affected

FMN2 (HGNC:14074): (formin 2) This gene is a member of the formin homology protein family. The encoded protein is thought to have essential roles in organization of the actin cytoskeleton and in cell polarity. This protein mediates the formation of an actin mesh that positions the spindle during oogenesis and also regulates the formation of actin filaments in the nucleus. This protein also forms a perinuclear actin/focal-adhesion system that regulates the shape and position of the nucleus during cell migration. Mutations in this gene have been associated with infertility and also with an autosomal recessive form of intellectual disability (MRT47). Alternatively spliced transcript variants have been identified. [provided by RefSeq, Jul 2017]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 1-240092805-T-C is Benign according to our data. Variant chr1-240092805-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 435216.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.003 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00387 (589/152240) while in subpopulation NFE AF= 0.00594 (404/67998). AF 95% confidence interval is 0.00546. There are 1 homozygotes in gnomad4. There are 278 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FMN2	NM_020066.5	c.696T>C	p.Pro232=	synonymous_variant	1/18	ENST00000319653.14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FMN2	ENST00000319653.14	c.696T>C	p.Pro232=	synonymous_variant	1/18	5	NM_020066.5	P1
FMN2	ENST00000447095.5	c.-87+24732T>C		intron_variant		3

Frequencies

GnomAD3 genomes AF: 0.00387 AC: 589 AN: 152122 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00101

Gnomad AMI AF: 0.0110

Gnomad AMR AF: 0.00392

Gnomad ASJ AF: 0.00518

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00395

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00594

Gnomad OTH AF: 0.00575

GnomAD3 exomes AF: 0.00378 AC: 728 AN: 192700 Hom.: 3 AF XY: 0.00381 AC XY: 400 AN XY: 105032

Gnomad AFR exome AF: 0.000943

Gnomad AMR exome AF: 0.00430

Gnomad ASJ exome AF: 0.00729

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000741

Gnomad FIN exome AF: 0.00395

Gnomad NFE exome AF: 0.00542

Gnomad OTH exome AF: 0.00435

GnomAD4 exome AF: 0.00465 AC: 6661 AN: 1433414 Hom.: 23 Cov.: 89 AF XY: 0.00451 AC XY: 3205 AN XY: 710578

Gnomad4 AFR exome AF: 0.000849

Gnomad4 AMR exome AF: 0.00427

Gnomad4 ASJ exome AF: 0.00709

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000132

Gnomad4 FIN exome AF: 0.00394

Gnomad4 NFE exome AF: 0.00528

Gnomad4 OTH exome AF: 0.00457

GnomAD4 genome AF: 0.00387 AC: 589 AN: 152240 Hom.: 1 Cov.: 33 AF XY: 0.00373 AC XY: 278 AN XY: 74438

Gnomad4 AFR AF: 0.00101

Gnomad4 AMR AF: 0.00392

Gnomad4 ASJ AF: 0.00518

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00395

Gnomad4 NFE AF: 0.00594

Gnomad4 OTH AF: 0.00569

Alfa AF: 0.00499 Hom.: 1

Bravo AF: 0.00365

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 31, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	FMN2: BP4, BP7, BS2 -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Nov 17, 2015

- -

FMN2-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 28, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
Cadd	Benign	8.0
Dann	Benign	0.67

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

LitVar

Other links and lift over

dbSNP: rs11583501; hg19: chr1-240256105;