chr1-240433914-G-T

Variant names:

• chr1-240433914-G-T
• rs9287237
• NM_020066.5:c.4911-4147G>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_020066.5(FMN2):​c.4911-4147G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.183 in 152,098 control chromosomes in the GnomAD database, including 2,759 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.18 (2759 hom., cov: 33)
• Consequence: FMN2 NM_020066.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.81
• Publications: 20 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.373 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FMN2	NM_020066.5	MANE Select	c.4911-4147G>T		intron	N/A	NP_064450.3
	FMN2	NM_001305424.2		c.4923-4147G>T		intron	N/A	NP_001292353.1
	FMN2	NM_001348094.2		c.2739-4147G>T		intron	N/A	NP_001335023.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FMN2	ENST00000319653.14	TSL:5 MANE Select	c.4911-4147G>T		intron	N/A	ENSP00000318884.9
	FMN2	ENST00000679980.1		c.1179-4147G>T		intron	N/A	ENSP00000505449.1
	FMN2	ENST00000681210.1		c.1131-4147G>T		intron	N/A	ENSP00000505131.1

Frequencies

GnomAD3 genomes AF: 0.183 AC: 27878 AN: 151980 Hom.: 2759 Cov.: 33

Gnomad AFR AF: 0.203

Gnomad AMI AF: 0.0901

Gnomad AMR AF: 0.159

Gnomad ASJ AF: 0.133

Gnomad EAS AF: 0.387

Gnomad SAS AF: 0.185

Gnomad FIN AF: 0.113

Gnomad MID AF: 0.177

Gnomad NFE AF: 0.176

Gnomad OTH AF: 0.206

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.183 AC: 27885 AN: 152098 Hom.: 2759 Cov.: 33 AF XY: 0.182 AC XY: 13543 AN XY: 74340

African (AFR) AF: 0.203 AC: 8419 AN: 41490

American (AMR) AF: 0.159 AC: 2429 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.133 AC: 460 AN: 3470

East Asian (EAS) AF: 0.387 AC: 1994 AN: 5154

South Asian (SAS) AF: 0.185 AC: 888 AN: 4812

European-Finnish (FIN) AF: 0.113 AC: 1192 AN: 10588

Middle Eastern (MID) AF: 0.184 AC: 54 AN: 294

European-Non Finnish (NFE) AF: 0.176 AC: 11935 AN: 67986

Other (OTH) AF: 0.205 AC: 432 AN: 2110

Alfa AF: 0.184 Hom.: 3992

Bravo AF: 0.189

Asia WGS AF: 0.250 AC: 868 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	7.3
DANN	Benign	0.83
PhyloP100		1.8
Mutation Taster		=100/0	polymorphism (auto)

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: rs9287237; hg19: chr1-240597214; COSMIC: COSV60452696;