chr1-240207698-A-G

Variant names:

• chr1-240207698-A-G
• rs199866405
• NM_020066.5:c.2886A>G

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_001305424.2(FMN2):​c.2898A>G​(p.Ala966Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0113 in 756,088 control chromosomes in the GnomAD database, including 189 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A966A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0057 (0 hom., cov: 0)
  • Exomes 𝑓: 0.012 (189 hom.)
• Consequence: FMN2 NM_001305424.2 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -2.99
• 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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 1-240207698-A-G is Benign according to our data. Variant chr1-240207698-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 435228.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.99 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 189 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001305424.2. 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.2886A>G	p.Ala962Ala	synonymous	Exon 5 of 18	NP_064450.3
	FMN2	NM_001305424.2		c.2898A>G	p.Ala966Ala	synonymous	Exon 6 of 19	NP_001292353.1
	FMN2	NM_001348094.2		c.1986+19436A>G		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.2886A>G	p.Ala962Ala	synonymous	Exon 5 of 18	ENSP00000318884.9
	FMN2	ENST00000679980.1		c.188+706A>G		intron	N/A	ENSP00000505449.1
	FMN2	ENST00000681210.1		c.285+19436A>G		intron	N/A	ENSP00000505131.1

Frequencies

GnomAD3 genomes AF: 0.00573 AC: 278 AN: 48554 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00369

Gnomad AMI AF: 0.00245

Gnomad AMR AF: 0.00489

Gnomad ASJ AF: 0.00160

Gnomad EAS AF: 0.00327

Gnomad SAS AF: 0.00733

Gnomad FIN AF: 0.00847

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00692

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0117 AC: 8256 AN: 707496 Hom.: 189 Cov.: 21 AF XY: 0.0121 AC XY: 4282 AN XY: 354284

African (AFR) AF: 0.00855 AC: 123 AN: 14388

American (AMR) AF: 0.00764 AC: 220 AN: 28790

Ashkenazi Jewish (ASJ) AF: 0.0349 AC: 407 AN: 11672

East Asian (EAS) AF: 0.0391 AC: 602 AN: 15410

South Asian (SAS) AF: 0.0111 AC: 512 AN: 46152

European-Finnish (FIN) AF: 0.0120 AC: 361 AN: 29964

Middle Eastern (MID) AF: 0.0253 AC: 46 AN: 1816

European-Non Finnish (NFE) AF: 0.0103 AC: 5464 AN: 531744

Other (OTH) AF: 0.0189 AC: 521 AN: 27560

GnomAD4 genome AF: 0.00572 AC: 278 AN: 48592 Hom.: 0 Cov.: 0 AF XY: 0.00599 AC XY: 137 AN XY: 22876

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

African (AFR) AF: 0.00368 AC: 40 AN: 10872

American (AMR) AF: 0.00488 AC: 20 AN: 4096

Ashkenazi Jewish (ASJ) AF: 0.00160 AC: 2 AN: 1252

East Asian (EAS) AF: 0.00326 AC: 5 AN: 1534

South Asian (SAS) AF: 0.00730 AC: 10 AN: 1370

European-Finnish (FIN) AF: 0.00847 AC: 21 AN: 2480

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 58

European-Non Finnish (NFE) AF: 0.00692 AC: 179 AN: 25878

Other (OTH) AF: 0.00 AC: 0 AN: 644

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0812 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	FMN2-related disorder (1)
-	-	1	Intellectual disability, autosomal recessive 47 (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	2.5
DANN	Benign	0.35
PhyloP100		-3.0
Mutation Taster		=100/0	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: rs199866405; hg19: chr1-240370998; COSMIC: COSV60425449; COSMIC: COSV60425449;