rs146681532

Positions:

• chr1-240093368-A-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_020066.5(FMN2):​c.1259A>C​(p.Lys420Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00473 in 1,612,976 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K420E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0032 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0049 (24 hom.)
• Consequence: FMN2 NM_020066.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 5.42

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010390341).
• BP6: Variant 1-240093368-A-C is Benign according to our data. Variant chr1-240093368-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 435219.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=5}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00323 (490/151908) while in subpopulation NFE AF= 0.00524 (356/67924). AF 95% confidence interval is 0.00479. There are 1 homozygotes in gnomad4. There are 216 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 24 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FMN2	NM_020066.5	c.1259A>C	p.Lys420Thr	missense_variant	1/18	ENST00000319653.14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FMN2	ENST00000319653.14	c.1259A>C	p.Lys420Thr	missense_variant	1/18	5	NM_020066.5	P1
FMN2	ENST00000447095.5	c.-87+25295A>C		intron_variant		3

Frequencies

GnomAD3 genomes AF: 0.00323 AC: 490 AN: 151786 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00104

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00249

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.00340

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00524

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00327 AC: 811 AN: 248114 Hom.: 3 AF XY: 0.00329 AC XY: 442 AN XY: 134412

Gnomad AFR exome AF: 0.000310

Gnomad AMR exome AF: 0.00238

Gnomad ASJ exome AF: 0.00130

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00229

Gnomad FIN exome AF: 0.00287

Gnomad NFE exome AF: 0.00497

Gnomad OTH exome AF: 0.00443

GnomAD4 exome AF: 0.00488 AC: 7134 AN: 1461068 Hom.: 24 Cov.: 88 AF XY: 0.00481 AC XY: 3499 AN XY: 726844

Gnomad4 AFR exome AF: 0.000419

Gnomad4 AMR exome AF: 0.00211

Gnomad4 ASJ exome AF: 0.00103

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00226

Gnomad4 FIN exome AF: 0.00328

Gnomad4 NFE exome AF: 0.00578

Gnomad4 OTH exome AF: 0.00336

GnomAD4 genome AF: 0.00323 AC: 490 AN: 151908 Hom.: 1 Cov.: 33 AF XY: 0.00291 AC XY: 216 AN XY: 74260

Gnomad4 AFR AF: 0.00104

Gnomad4 AMR AF: 0.00249

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00270

Gnomad4 FIN AF: 0.00340

Gnomad4 NFE AF: 0.00524

Gnomad4 OTH AF: 0.00143

Alfa AF: 0.00419 Hom.: 0

Bravo AF: 0.00301

TwinsUK AF: 0.00728 AC: 27

ALSPAC AF: 0.00727 AC: 28

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00640 AC: 55

ExAC AF: 0.00334 AC: 405

EpiCase AF: 0.00382

EpiControl AF: 0.00368

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Sep 11, 2017	- -
Likely 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	Jun 01, 2024	FMN2: BS2 -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Mar 28, 2019

- -

FMN2-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 28, 2022

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

Intellectual disability, autosomal recessive 47 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

May 21, 2020

Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as likely benign. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0106 - This gene is known to be associated with autosomal recessive disease. (N) 0200 - Variant is predicted to result in a missense amino acid change from lysine to threonine (exon1). (N) 0251 - Variant is heterozygous. (N) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (906 heterozygotes, 3 homozygotes). (P) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (5 heterozygotes, 0 homozygotes). (N) 0502 - Missense variant with conflicting in silico predictions. (N) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (N) 0705 - No comparable variants have previous evidence for pathogenicity. (N) 0807 - Variant has not previously been reported in a clinical context. (N) 0905 - No segregation evidence has been identified for this variant. (N) 1007 - No published functional evidence has been identified for this variant. (N) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.090
CADD	Benign	22
DANN	Benign	0.95
DEOGEN2	Uncertain	0.55	D
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.78	T
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.010	T
MetaSVM	Uncertain	-0.25	T
MutationAssessor	Uncertain	2.4	M
MutationTaster	Benign	0.69	D
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-3.8	D
REVEL	Uncertain	0.58
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.018	D
Polyphen		0.99	D
Vest4		0.30
MVP		0.78
MPC		0.95
ClinPred		0.067	T
GERP RS		3.0
Varity_R		0.72
gMVP		0.45

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: rs146681532; hg19: chr1-240256668;