1-240092201-A-C

Variant names:

• chr1-240092201-A-C
• rs745730585
• NM_020066.5:c.92A>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_020066.5(FMN2):​c.92A>C​(p.Asp31Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00000128 in 1,562,982 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D31G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000068 (0 hom., cov: 33)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: FMN2 NM_020066.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.44
• Publications: 0 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), G2P, Ambry Genetics
• autosomal recessive non-syndromic intellectual disability

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20302153).

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.92A>C	p.Asp31Ala	missense	Exon 1 of 18	NP_064450.3
	FMN2	NM_001305424.2		c.92A>C	p.Asp31Ala	missense	Exon 1 of 19	NP_001292353.1
	FMN2	NM_001348094.2		c.92A>C	p.Asp31Ala	missense	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.92A>C	p.Asp31Ala	missense	Exon 1 of 18	ENSP00000318884.9	Q9NZ56-1
	FMN2	ENST00000447095.5	TSL:3	c.-87+24128A>C		intron	N/A	ENSP00000409308.1	B0QZA8

Frequencies

GnomAD3 genomes AF: 0.00000682 AC: 1 AN: 146534 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000150

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 7.06e-7 AC: 1 AN: 1416448 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 701044

African (AFR) AF: 0.00 AC: 0 AN: 32774

American (AMR) AF: 0.00 AC: 0 AN: 40180

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24688

East Asian (EAS) AF: 0.00 AC: 0 AN: 38200

South Asian (SAS) AF: 0.00 AC: 0 AN: 81794

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47686

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5244

European-Non Finnish (NFE) AF: 9.19e-7 AC: 1 AN: 1087582

Other (OTH) AF: 0.00 AC: 0 AN: 58300

GnomAD4 genome AF: 0.00000682 AC: 1 AN: 146534 Hom.: 0 Cov.: 33 AF XY: 0.0000140 AC XY: 1 AN XY: 71264

African (AFR) AF: 0.00 AC: 0 AN: 39694

American (AMR) AF: 0.00 AC: 0 AN: 14806

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3410

East Asian (EAS) AF: 0.00 AC: 0 AN: 4842

South Asian (SAS) AF: 0.00 AC: 0 AN: 4558

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9444

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 304

European-Non Finnish (NFE) AF: 0.0000150 AC: 1 AN: 66576

Other (OTH) AF: 0.00 AC: 0 AN: 2014

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Uncertain	24
DANN	Benign	0.75
DEOGEN2	Benign	0.36	T
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.16
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.45	T
M_CAP	Uncertain	0.097	D
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.8	L
PhyloP100		6.4
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-4.2	D
REVEL	Benign	0.14
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.010	D
Polyphen		0.030	B
Vest4		0.28
MutPred		0.055		Gain of MoRF binding (P = 0.0338)
MVP		0.27
MPC		0.98
ClinPred		0.90	D
GERP RS		3.9
PromoterAI		0.034	Neutral
Varity_R		0.49
gMVP		0.14
Mutation Taster		=92/8	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: rs745730585; hg19: chr1-240255501;