rs12091371

Variant names:

• chr1-240441752-G-A
• rs12091371
• NM_020066.5:c.5060+3542G>A

Variant summary

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

The NM_020066.5(FMN2):​c.5060+3542G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.176 in 151,526 control chromosomes in the GnomAD database, including 4,018 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 (4018 hom., cov: 30)
• Consequence: FMN2 NM_020066.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0460
• Publications: 11 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=-0.94).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.396 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FMN2	NM_020066.5	c.5060+3542G>A		intron_variant	Intron 16 of 17	ENST00000319653.14	NP_064450.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FMN2	ENST00000319653.14	c.5060+3542G>A		intron_variant	Intron 16 of 17	5	NM_020066.5	ENSP00000318884.9

Frequencies

GnomAD3 genomes AF: 0.176 AC: 26690 AN: 151410 Hom.: 4010 Cov.: 30

Gnomad AFR AF: 0.401

Gnomad AMI AF: 0.0991

Gnomad AMR AF: 0.122

Gnomad ASJ AF: 0.0905

Gnomad EAS AF: 0.303

Gnomad SAS AF: 0.175

Gnomad FIN AF: 0.0214

Gnomad MID AF: 0.150

Gnomad NFE AF: 0.0726

Gnomad OTH AF: 0.169

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

GnomAD4 genome AF: 0.176 AC: 26723 AN: 151526 Hom.: 4018 Cov.: 30 AF XY: 0.174 AC XY: 12884 AN XY: 74008

African (AFR) AF: 0.401 AC: 16527 AN: 41212

American (AMR) AF: 0.122 AC: 1854 AN: 15234

Ashkenazi Jewish (ASJ) AF: 0.0905 AC: 313 AN: 3460

East Asian (EAS) AF: 0.303 AC: 1554 AN: 5128

South Asian (SAS) AF: 0.174 AC: 832 AN: 4790

European-Finnish (FIN) AF: 0.0214 AC: 224 AN: 10454

Middle Eastern (MID) AF: 0.144 AC: 42 AN: 292

European-Non Finnish (NFE) AF: 0.0726 AC: 4934 AN: 67940

Other (OTH) AF: 0.167 AC: 353 AN: 2108

Alfa AF: 0.128 Hom.: 4367

Bravo AF: 0.196

Asia WGS AF: 0.217 AC: 755 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.93
DANN	Benign	0.23
PhyloP100		0.046
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: rs12091371; hg19: chr1-240605052;