rs143796494

Positions:

• chr1-240472447-T-G

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_020066.5(FMN2):​c.5136T>G​(p.Ser1712=) 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

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]

ACMG classification

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id is 435232.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-240472447-T-G is described in Lovd as [Likely_benign].
• 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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FMN2	NM_020066.5	c.5136T>G	p.Ser1712=	synonymous_variant	17/18	ENST00000319653.14	NP_064450.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FMN2	ENST00000319653.14	c.5136T>G	p.Ser1712=	synonymous_variant	17/18	5	NM_020066.5	ENSP00000318884	P1

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

GnomAD3 exomes AF: 0.00323 AC: 783 AN: 242460 Hom.: 3 AF XY: 0.00330 AC XY: 432 AN XY: 130850

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 SAS 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

Gnomad4 AFR exome AF: 0.000394

Gnomad4 AMR exome AF: 0.00197

Gnomad4 ASJ exome AF: 0.000348

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000120

Gnomad4 FIN exome AF: 0.00596

Gnomad4 NFE exome AF: 0.00479

Gnomad4 OTH exome AF: 0.00429

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

Gnomad4 AFR AF: 0.000625

Gnomad4 AMR AF: 0.00392

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00442

Gnomad4 NFE AF: 0.00506

Gnomad4 OTH AF: 0.00236

Alfa AF: 0.00372 Hom.: 0

Bravo AF: 0.00306

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	FMN2: BP4, BP7, BS2 -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Sep 30, 2016

- -

Intellectual disability, autosomal recessive 47 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Mar 02, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	7.3
DANN	Benign	0.75

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

Publications

LitVar

Other links and lift over

dbSNP: rs143796494; hg19: chr1-240635747;