rs112904598

Variant names:

• chr1-240092472-C-T
• rs112904598
• NM_020066.5:c.363C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_020066.5(FMN2):​c.363C>T​(p.Leu121Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00289 in 1,609,000 control chromosomes in the GnomAD database, including 138 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (62 hom., cov: 33)
  • Exomes 𝑓: 0.0016 (76 hom.)
• Consequence: FMN2 NM_020066.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.537
• Publications: 1 publications found

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]

FMN2 Gene-Disease associations (from GenCC):

• intellectual disability, autosomal recessive 47

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• autosomal recessive non-syndromic intellectual disability

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 1-240092472-C-T is Benign according to our data. Variant chr1-240092472-C-T is described in ClinVar as Benign. ClinVar VariationId is 777107.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.537 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0515 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020066.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FMN2	NM_020066.5	MANE Select	c.363C>T	p.Leu121Leu	synonymous	Exon 1 of 18	NP_064450.3
	FMN2	NM_001305424.2		c.363C>T	p.Leu121Leu	synonymous	Exon 1 of 19	NP_001292353.1
	FMN2	NM_001348094.2		c.363C>T	p.Leu121Leu	synonymous	Exon 1 of 15	NP_001335023.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FMN2	ENST00000319653.14	TSL:5 MANE Select	c.363C>T	p.Leu121Leu	synonymous	Exon 1 of 18	ENSP00000318884.9	Q9NZ56-1
	FMN2	ENST00000447095.5	TSL:3	c.-87+24399C>T		intron	N/A	ENSP00000409308.1	B0QZA8

Frequencies

GnomAD3 genomes AF: 0.0153 AC: 2319 AN: 152044 Hom.: 62 Cov.: 33

Gnomad AFR AF: 0.0533

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00478

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000623

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.0115

GnomAD2 exomes AF: 0.00369 AC: 871 AN: 236152 AF XY: 0.00275

Gnomad AFR exome AF: 0.0543

Gnomad AMR exome AF: 0.00240

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000569

Gnomad OTH exome AF: 0.00172

GnomAD4 exome AF: 0.00159 AC: 2319 AN: 1456838 Hom.: 76 Cov.: 89 AF XY: 0.00132 AC XY: 954 AN XY: 724352

African (AFR) AF: 0.0572 AC: 1910 AN: 33390

American (AMR) AF: 0.00286 AC: 126 AN: 44014

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25968

East Asian (EAS) AF: 0.00 AC: 0 AN: 39520

South Asian (SAS) AF: 0.000152 AC: 13 AN: 85584

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52650

Middle Eastern (MID) AF: 0.00156 AC: 9 AN: 5768

European-Non Finnish (NFE) AF: 0.0000442 AC: 49 AN: 1109806

Other (OTH) AF: 0.00353 AC: 212 AN: 60138

GnomAD4 genome AF: 0.0153 AC: 2324 AN: 152162 Hom.: 62 Cov.: 33 AF XY: 0.0149 AC XY: 1109 AN XY: 74392

African (AFR) AF: 0.0533 AC: 2213 AN: 41512

American (AMR) AF: 0.00477 AC: 73 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5116

South Asian (SAS) AF: 0.000623 AC: 3 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00342 AC: 1 AN: 292

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 68016

Other (OTH) AF: 0.0114 AC: 24 AN: 2114

Alfa AF: 0.00681 Hom.: 18

Bravo AF: 0.0172

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	14
DANN	Benign	0.94
PhyloP100		0.54
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs112904598; hg19: chr1-240255772; COSMIC: COSV60432109;