chr1-240333921-C-T

Variant names:

• chr1-240333921-C-T
• rs150801382
• NM_020066.5:c.4619C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_020066.5(FMN2):​c.4619C>T​(p.Ser1540Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00268 in 1,610,086 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0021 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0027 (7 hom.)
• Consequence: FMN2 NM_020066.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:6
• Conservation: PhyloP100: 4.99
• Publications: 6 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008076876).
• BP6: Variant 1-240333921-C-T is Benign according to our data. Variant chr1-240333921-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 435231.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0021 (320/152188) while in subpopulation NFE AF = 0.00347 (236/67974). AF 95% confidence interval is 0.00311. There are 0 homozygotes in GnomAd4. There are 140 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 7 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FMN2	NM_020066.5	MANE Select	c.4619C>T	p.Ser1540Leu	missense	Exon 12 of 18	NP_064450.3
	FMN2	NM_001305424.2		c.4631C>T	p.Ser1544Leu	missense	Exon 13 of 19	NP_001292353.1
	FMN2	NM_001348094.2		c.2540C>T	p.Ser847Leu	missense	Exon 10 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.4619C>T	p.Ser1540Leu	missense	Exon 12 of 18	ENSP00000318884.9
	FMN2	ENST00000679980.1		c.887C>T	p.Ser296Leu	missense	Exon 8 of 14	ENSP00000505449.1
	FMN2	ENST00000681210.1		c.839C>T	p.Ser280Leu	missense	Exon 9 of 15	ENSP00000505131.1

Frequencies

GnomAD3 genomes AF: 0.00210 AC: 320 AN: 152070 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000579

Gnomad AMI AF: 0.0132

Gnomad AMR AF: 0.00229

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000851

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00347

Gnomad OTH AF: 0.00192

GnomAD2 exomes AF: 0.00194 AC: 483 AN: 248858 AF XY: 0.00204

Gnomad AFR exome AF: 0.000623

Gnomad AMR exome AF: 0.00257

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000556

Gnomad NFE exome AF: 0.00321

Gnomad OTH exome AF: 0.00149

GnomAD4 exome AF: 0.00274 AC: 4001 AN: 1457898 Hom.: 7 Cov.: 30 AF XY: 0.00275 AC XY: 1996 AN XY: 724838

African (AFR) AF: 0.000569 AC: 19 AN: 33384

American (AMR) AF: 0.00263 AC: 117 AN: 44456

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26038

East Asian (EAS) AF: 0.00 AC: 0 AN: 39526

South Asian (SAS) AF: 0.0000824 AC: 7 AN: 84918

European-Finnish (FIN) AF: 0.000601 AC: 32 AN: 53258

Middle Eastern (MID) AF: 0.000526 AC: 3 AN: 5706

European-Non Finnish (NFE) AF: 0.00332 AC: 3685 AN: 1110402

Other (OTH) AF: 0.00229 AC: 138 AN: 60210

GnomAD4 genome AF: 0.00210 AC: 320 AN: 152188 Hom.: 0 Cov.: 33 AF XY: 0.00188 AC XY: 140 AN XY: 74394

African (AFR) AF: 0.000577 AC: 24 AN: 41564

American (AMR) AF: 0.00229 AC: 35 AN: 15280

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.000851 AC: 9 AN: 10574

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

European-Non Finnish (NFE) AF: 0.00347 AC: 236 AN: 67974

Other (OTH) AF: 0.00190 AC: 4 AN: 2106

Alfa AF: 0.00171 Hom.: 5

Bravo AF: 0.00222

TwinsUK AF: 0.00270 AC: 10

ALSPAC AF: 0.00415 AC: 16

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00326 AC: 28

ExAC AF: 0.00178 AC: 216

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	1	1	not specified (2)
-	-	1	FMN2-related disorder (1)
-	-	1	Inborn genetic diseases (1)
-	1	-	Intellectual disability, autosomal recessive 47 (1)
-	-	1	Neurodevelopmental abnormality (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.67
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Benign	-0.41
CADD	Pathogenic	27
DANN	Uncertain	1.0
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.48	T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.0081	T
MetaSVM	Benign	-1.1	T
PhyloP100		5.0
Sift4G	Uncertain	0.021	D
Vest4		0.36
MVP		0.79
ClinPred		0.055	T
GERP RS		5.8
Varity_R		0.53
Mutation Taster		=41/59	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs150801382; hg19: chr1-240497221; COSMIC: COSV60429273; COSMIC: COSV60429273;