1-240207986-T-C

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP7

The NM_020066.5(FMN2):​c.3174T>C​(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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. L1058L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 1)
  • Exomes 𝑓: 0.0000086 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: FMN2 NM_020066.5 synonymous
• Clinical Significance: Not reported in ClinVar
• 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: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• autosomal recessive non-syndromic intellectual disability

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.06).
• 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FMN2	NM_020066.5	MANE Select	c.3174T>C	p.Leu1058Leu	synonymous	Exon 5 of 18	NP_064450.3
	FMN2	NM_001305424.2		c.3186T>C	p.Leu1062Leu	synonymous	Exon 6 of 19	NP_001292353.1
	FMN2	NM_001348094.2		c.1986+19724T>C		intron	N/A	NP_001335023.1

Ensembl Transcripts

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

Frequencies

GnomAD3 genomes Cov.: 1

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000865 AC: 1 AN: 115646 Hom.: 0 Cov.: 0 AF XY: 0.0000158 AC XY: 1 AN XY: 63190

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

African (AFR) AF: 0.00 AC: 0 AN: 2390

American (AMR) AF: 0.00 AC: 0 AN: 4134

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2164

East Asian (EAS) AF: 0.00 AC: 0 AN: 3814

South Asian (SAS) AF: 0.00 AC: 0 AN: 19486

European-Finnish (FIN) AF: 0.0000680 AC: 1 AN: 14702

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 63420

Other (OTH) AF: 0.00 AC: 0 AN: 5200

⚠️ 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 Cov.: 1

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.1
CADD	Benign	0.69
DANN	Benign	0.41
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;