rs143796494

Variant names:

• chr1-240472447-T-G
• rs143796494
• NM_020066.5:c.5136T>G

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_020066.5(FMN2):​c.5136T>G​(p.Ser1712Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00403 in 1,600,494 control chromosomes in the GnomAD database, including 27 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0032 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0041 (25 hom.)
• Consequence: FMN2 NM_020066.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.353
• Publications: 2 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 1-240472447-T-G is Benign according to our data. Variant chr1-240472447-T-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 435232.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.353 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00318 (484/152378) while in subpopulation NFE AF = 0.00506 (344/68040). AF 95% confidence interval is 0.00462. There are 2 homozygotes in GnomAd4. There are 206 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 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.5136T>G	p.Ser1712Ser	synonymous	Exon 17 of 18	NP_064450.3
	FMN2	NM_001305424.2		c.5148T>G	p.Ser1716Ser	synonymous	Exon 18 of 19	NP_001292353.1
	FMN2	NM_001348094.2		c.2964T>G	p.Ser988Ser	synonymous	Exon 14 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.5136T>G	p.Ser1712Ser	synonymous	Exon 17 of 18	ENSP00000318884.9	Q9NZ56-1
	FMN2	ENST00000543681.2	TSL:1	n.2745T>G		non_coding_transcript_exon	Exon 2 of 3
	FMN2	ENST00000679980.1		c.1404T>G	p.Ser468Ser	synonymous	Exon 13 of 14	ENSP00000505449.1	A0A7P0T994

Frequencies

GnomAD3 genomes AF: 0.00317 AC: 483 AN: 152260 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000627

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00386

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00442

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00506

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00323 AC: 783 AN: 242460 AF XY: 0.00330

Gnomad AFR exome AF: 0.000752

Gnomad AMR exome AF: 0.00206

Gnomad ASJ exome AF: 0.000205

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00497

Gnomad NFE exome AF: 0.00508

Gnomad OTH exome AF: 0.00504

GnomAD4 exome AF: 0.00412 AC: 5971 AN: 1448116 Hom.: 25 Cov.: 27 AF XY: 0.00412 AC XY: 2966 AN XY: 720406

African (AFR) AF: 0.000394 AC: 13 AN: 32964

American (AMR) AF: 0.00197 AC: 84 AN: 42674

Ashkenazi Jewish (ASJ) AF: 0.000348 AC: 9 AN: 25884

East Asian (EAS) AF: 0.00 AC: 0 AN: 39406

South Asian (SAS) AF: 0.0000120 AC: 1 AN: 83626

European-Finnish (FIN) AF: 0.00596 AC: 318 AN: 53330

Middle Eastern (MID) AF: 0.000350 AC: 2 AN: 5716

European-Non Finnish (NFE) AF: 0.00479 AC: 5287 AN: 1104566

Other (OTH) AF: 0.00429 AC: 257 AN: 59950

GnomAD4 genome AF: 0.00318 AC: 484 AN: 152378 Hom.: 2 Cov.: 33 AF XY: 0.00276 AC XY: 206 AN XY: 74516

African (AFR) AF: 0.000625 AC: 26 AN: 41598

American (AMR) AF: 0.00392 AC: 60 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00442 AC: 47 AN: 10626

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

European-Non Finnish (NFE) AF: 0.00506 AC: 344 AN: 68040

Other (OTH) AF: 0.00236 AC: 5 AN: 2116

Alfa AF: 0.00372 Hom.: 0

Bravo AF: 0.00306

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Intellectual disability, autosomal recessive 47 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	7.3
DANN	Benign	0.75
PhyloP100		0.35
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: rs143796494; hg19: chr1-240635747;