1-240092887-G-A

Variant names:

• chr1-240092887-G-A
• rs147858483
• NM_020066.5:c.778G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_020066.5(FMN2):​c.778G>A​(p.Ala260Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0016 in 1,517,818 control chromosomes in the GnomAD database, including 37 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A260V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0090 (18 hom., cov: 33)
  • Exomes 𝑓: 0.00077 (19 hom.)
• Consequence: FMN2 NM_020066.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.324
• 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0028507411).
• BP6: Variant 1-240092887-G-A is Benign according to our data. Variant chr1-240092887-G-A is described in ClinVar as Benign. ClinVar VariationId is 377373.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00903 (1375/152216) while in subpopulation AFR AF = 0.031 (1289/41568). AF 95% confidence interval is 0.0296. There are 18 homozygotes in GnomAd4. There are 666 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 18 AR gene

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.778G>A	p.Ala260Thr	missense	Exon 1 of 18	NP_064450.3
	FMN2	NM_001305424.2		c.778G>A	p.Ala260Thr	missense	Exon 1 of 19	NP_001292353.1
	FMN2	NM_001348094.2		c.778G>A	p.Ala260Thr	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.778G>A	p.Ala260Thr	missense	Exon 1 of 18	ENSP00000318884.9
	FMN2	ENST00000447095.5	TSL:3	c.-87+24814G>A		intron	N/A	ENSP00000409308.1

Frequencies

GnomAD3 genomes AF: 0.00897 AC: 1365 AN: 152102 Hom.: 17 Cov.: 33

Gnomad AFR AF: 0.0309

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00406

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: 0.000132

Gnomad OTH AF: 0.00718

GnomAD2 exomes AF: 0.00218 AC: 242 AN: 111134 AF XY: 0.00192

Gnomad AFR exome AF: 0.0304

Gnomad AMR exome AF: 0.00207

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000102

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000214

Gnomad OTH exome AF: 0.00117

GnomAD4 exome AF: 0.000770 AC: 1052 AN: 1365602 Hom.: 19 Cov.: 88 AF XY: 0.000678 AC XY: 456 AN XY: 672450

African (AFR) AF: 0.0266 AC: 821 AN: 30912

American (AMR) AF: 0.00194 AC: 63 AN: 32456

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23472

East Asian (EAS) AF: 0.0000281 AC: 1 AN: 35626

South Asian (SAS) AF: 0.0000396 AC: 3 AN: 75732

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35372

Middle Eastern (MID) AF: 0.000750 AC: 3 AN: 4002

European-Non Finnish (NFE) AF: 0.0000579 AC: 62 AN: 1071326

Other (OTH) AF: 0.00175 AC: 99 AN: 56704

GnomAD4 genome AF: 0.00903 AC: 1375 AN: 152216 Hom.: 18 Cov.: 33 AF XY: 0.00895 AC XY: 666 AN XY: 74404

African (AFR) AF: 0.0310 AC: 1289 AN: 41568

American (AMR) AF: 0.00405 AC: 62 AN: 15308

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5104

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 67992

Other (OTH) AF: 0.00710 AC: 15 AN: 2112

Alfa AF: 0.00394 Hom.: 1

Bravo AF: 0.00958

ESP6500AA AF: 0.0149 AC: 40

ESP6500EA AF: 0.000338 AC: 2

ExAC AF: 0.000860 AC: 71

Asia WGS AF: 0.00145 AC: 5 AN: 3472

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Dec 30, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	8.5
DANN	Benign	0.94
DEOGEN2	Benign	0.065	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.041	N
LIST_S2	Benign	0.38	T
MetaRNN	Benign	0.0029	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L
PhyloP100		0.32
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-0.89	N
REVEL	Benign	0.026
Sift	Benign	0.29	T
Sift4G	Benign	0.39	T
Polyphen		0.0	B
Vest4		0.083
MVP		0.40
MPC		0.77
ClinPred		0.0019	T
GERP RS		-5.5
Varity_R		0.034
gMVP		0.062
Mutation Taster		=98/2	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: rs147858483; hg19: chr1-240256187; COSMIC: COSV106102110;