1-240092480-C-T

Variant names:

• chr1-240092480-C-T
• rs1283481751
• NM_020066.5:c.371C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The ENST00000319653.14(FMN2):​c.371C>T​(p.Ser124Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,455,918 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: FMN2 ENST00000319653.14 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.00
• 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: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• autosomal recessive non-syndromic intellectual disability

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000319653.14. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FMN2	NM_020066.5	MANE Select	c.371C>T	p.Ser124Leu	missense	Exon 1 of 18	NP_064450.3
	FMN2	NM_001305424.2		c.371C>T	p.Ser124Leu	missense	Exon 1 of 19	NP_001292353.1
	FMN2	NM_001348094.2		c.371C>T	p.Ser124Leu	missense	Exon 1 of 15	NP_001335023.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FMN2	ENST00000319653.14	TSL:5 MANE Select	c.371C>T	p.Ser124Leu	missense	Exon 1 of 18	ENSP00000318884.9
	FMN2	ENST00000447095.5	TSL:3	c.-87+24407C>T		intron	N/A	ENSP00000409308.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00 AC: 0 AN: 233972 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1455918 Hom.: 0 Cov.: 88 AF XY: 0.00000276 AC XY: 2 AN XY: 723758

African (AFR) AF: 0.00 AC: 0 AN: 33374

American (AMR) AF: 0.00 AC: 0 AN: 43870

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25946

East Asian (EAS) AF: 0.00 AC: 0 AN: 39492

South Asian (SAS) AF: 0.00 AC: 0 AN: 85538

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52514

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1109310

Other (OTH) AF: 0.00 AC: 0 AN: 60108

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Benign	-0.031	T
BayesDel_noAF	Benign	-0.28
CADD	Uncertain	26
DANN	Benign	0.97
DEOGEN2	Uncertain	0.53	D
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.88	D
M_CAP	Pathogenic	0.69	D
MetaRNN	Uncertain	0.49	T
MetaSVM	Benign	-0.47	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		7.0
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-3.7	D
REVEL	Uncertain	0.30
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.99	D
Vest4		0.36
MutPred		0.13		Loss of phosphorylation at S124 (P = 0.0229)
MVP		0.33
MPC		0.71
ClinPred		0.99	D
GERP RS		4.3
Varity_R		0.74
gMVP		0.15
Mutation Taster		=90/10	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: rs1283481751; hg19: chr1-240255780;