rs200287374

Variant names:

• chr1-240207986-T-A
• rs200287374
• NM_020066.5:c.3174T>A

Your query was ambiguous. Multiple possible variants found:

• chr1-240207986-T-A
• chr1-240207986-T-C
• chr1-240207986-T-G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6_Very_Strong BP7

The NM_020066.5(FMN2):​c.3174T>A​(p.Leu1058Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 1)
  • Exomes 𝑓: 0.00093 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: FMN2 NM_020066.5 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -8.07
• Publications: 0 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: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• 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 (BayesDel_noAF=-1.02).
• BP6: Variant 1-240207986-T-A is Benign according to our data. Variant chr1-240207986-T-A is described in ClinVar as Likely_benign. ClinVar VariationId is 435229.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-8.07 with no splicing effect.

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.3174T>A	p.Leu1058Leu	synonymous	Exon 5 of 18	NP_064450.3
	FMN2	NM_001305424.2		c.3186T>A	p.Leu1062Leu	synonymous	Exon 6 of 19	NP_001292353.1
	FMN2	NM_001348094.2		c.1986+19724T>A		intron	N/A	NP_001335023.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FMN2	ENST00000319653.14	TSL:5 MANE Select	c.3174T>A	p.Leu1058Leu	synonymous	Exon 5 of 18	ENSP00000318884.9	Q9NZ56-1
	FMN2	ENST00000679980.1		c.188+994T>A		intron	N/A	ENSP00000505449.1	A0A7P0T994
	FMN2	ENST00000681210.1		c.285+19724T>A		intron	N/A	ENSP00000505131.1	A0A7P0Z432

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 3806 Hom.: 0 Cov.: 1

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000807 AC: 11 AN: 13632 AF XY: 0.000761

Gnomad AFR exome AF: 0.0113

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.0122

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000545

Gnomad OTH exome AF: 0.0127

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000935 AC: 108 AN: 115560 Hom.: 0 Cov.: 0 AF XY: 0.000950 AC XY: 60 AN XY: 63138

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00209 AC: 5 AN: 2388

American (AMR) AF: 0.00 AC: 0 AN: 4130

Ashkenazi Jewish (ASJ) AF: 0.00185 AC: 4 AN: 2162

East Asian (EAS) AF: 0.000788 AC: 3 AN: 3806

South Asian (SAS) AF: 0.000308 AC: 6 AN: 19478

European-Finnish (FIN) AF: 0.000272 AC: 4 AN: 14692

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 336

European-Non Finnish (NFE) AF: 0.00120 AC: 76 AN: 63372

Other (OTH) AF: 0.00192 AC: 10 AN: 5196

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 3806 Hom.: 0 Cov.: 1 AF XY: 0.00 AC XY: 0 AN XY: 2000

African (AFR) AF: 0.00 AC: 0 AN: 576

American (AMR) AF: 0.00 AC: 0 AN: 472

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 150

East Asian (EAS) AF: 0.00 AC: 0 AN: 72

South Asian (SAS) AF: 0.00 AC: 0 AN: 46

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 210

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 2210

Other (OTH) AF: 0.00 AC: 0 AN: 60

Alfa AF: 0.00155 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	FMN2-related disorder (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.60
DANN	Benign	0.51
PhyloP100		-8.1
Mutation Taster		=99/1	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: rs200287374; hg19: chr1-240371286;