rs147858483

Positions:

• chr1-240092887-G-A

Variant summary

Our verdict is Benign. Variant got -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. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• 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

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]

ACMG classification

Verdict is Benign. Variant got -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 id 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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 18 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FMN2	NM_020066.5	c.778G>A	p.Ala260Thr	missense_variant	1/18	ENST00000319653.14	NP_064450.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FMN2	ENST00000319653.14	c.778G>A	p.Ala260Thr	missense_variant	1/18	5	NM_020066.5	ENSP00000318884	P1
FMN2	ENST00000447095.5	c.-87+24814G>A		intron_variant		3		ENSP00000409308

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

GnomAD3 exomes AF: 0.00218 AC: 242 AN: 111134 Hom.: 3 AF XY: 0.00192 AC XY: 116 AN XY: 60556

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 SAS exome AF: 0.0000558

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

Gnomad4 AFR exome AF: 0.0266

Gnomad4 AMR exome AF: 0.00194

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000281

Gnomad4 SAS exome AF: 0.0000396

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000579

Gnomad4 OTH exome AF: 0.00175

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

Gnomad4 AFR AF: 0.0310

Gnomad4 AMR AF: 0.00405

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.00710

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

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Dec 30, 2016	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

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
MutationTaster	Benign	1.0	N
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

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

Publications

LitVar

Other links and lift over

dbSNP: rs147858483; hg19: chr1-240256187;