1-240092805-T-C

Variant names:

• chr1-240092805-T-C
• rs11583501
• NM_020066.5:c.696T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_020066.5(FMN2):​c.696T>C​(p.Pro232Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00457 in 1,585,654 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0039 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0046 (23 hom.)
• Consequence: FMN2 NM_020066.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.00300
• Publications: 1 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 1-240092805-T-C is Benign according to our data. Variant chr1-240092805-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 435216.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.003 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00387 (589/152240) while in subpopulation NFE AF = 0.00594 (404/67998). AF 95% confidence interval is 0.00546. There are 1 homozygotes in GnomAd4. There are 278 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 23 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.696T>C	p.Pro232Pro	synonymous	Exon 1 of 18	NP_064450.3
	FMN2	NM_001305424.2		c.696T>C	p.Pro232Pro	synonymous	Exon 1 of 19	NP_001292353.1
	FMN2	NM_001348094.2		c.696T>C	p.Pro232Pro	synonymous	Exon 1 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.696T>C	p.Pro232Pro	synonymous	Exon 1 of 18	ENSP00000318884.9
	FMN2	ENST00000447095.5	TSL:3	c.-87+24732T>C		intron	N/A	ENSP00000409308.1

Frequencies

GnomAD3 genomes AF: 0.00387 AC: 589 AN: 152122 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00101

Gnomad AMI AF: 0.0110

Gnomad AMR AF: 0.00392

Gnomad ASJ AF: 0.00518

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00395

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00594

Gnomad OTH AF: 0.00575

GnomAD2 exomes AF: 0.00378 AC: 728 AN: 192700 AF XY: 0.00381

Gnomad AFR exome AF: 0.000943

Gnomad AMR exome AF: 0.00430

Gnomad ASJ exome AF: 0.00729

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00395

Gnomad NFE exome AF: 0.00542

Gnomad OTH exome AF: 0.00435

GnomAD4 exome AF: 0.00465 AC: 6661 AN: 1433414 Hom.: 23 Cov.: 89 AF XY: 0.00451 AC XY: 3205 AN XY: 710578

African (AFR) AF: 0.000849 AC: 28 AN: 32980

American (AMR) AF: 0.00427 AC: 170 AN: 39816

Ashkenazi Jewish (ASJ) AF: 0.00709 AC: 181 AN: 25514

East Asian (EAS) AF: 0.00 AC: 0 AN: 38424

South Asian (SAS) AF: 0.000132 AC: 11 AN: 83614

European-Finnish (FIN) AF: 0.00394 AC: 197 AN: 49974

Middle Eastern (MID) AF: 0.000391 AC: 2 AN: 5110

European-Non Finnish (NFE) AF: 0.00528 AC: 5801 AN: 1098694

Other (OTH) AF: 0.00457 AC: 271 AN: 59288

GnomAD4 genome AF: 0.00387 AC: 589 AN: 152240 Hom.: 1 Cov.: 33 AF XY: 0.00373 AC XY: 278 AN XY: 74438

African (AFR) AF: 0.00101 AC: 42 AN: 41554

American (AMR) AF: 0.00392 AC: 60 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00518 AC: 18 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5140

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.00395 AC: 42 AN: 10624

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

European-Non Finnish (NFE) AF: 0.00594 AC: 404 AN: 67998

Other (OTH) AF: 0.00569 AC: 12 AN: 2108

Alfa AF: 0.00499 Hom.: 1

Bravo AF: 0.00365

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	FMN2-related disorder (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	8.0
DANN	Benign	0.67
PhyloP100		-0.0030
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: rs11583501; hg19: chr1-240256105;