rs758726356

Variant names:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 2P and 12B. PM4BP6_Very_StrongBS1

The NM_001305424.2(FMN2):c.2856_2888delACCCGGAGCGGCAATACCCCCTCCGCCCCCTCT(p.Pro953_Leu963del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. L952L) has been classified as Benign.

Frequency

Genomes: 𝑓 0.0077 ( 0 hom., cov: 0)

Exomes 𝑓: 0.0045 ( 32 hom. )

Failed GnomAD Quality Control

Consequence

FMN2
NM_001305424.2 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 2.82

Publications

0 publications found

Variant links:

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

FMN2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

PM4

Nonframeshift variant in NON repetitive region in NM_001305424.2.

BP6

Variant 1-240207641-TCCTCCGCCCCCTCTACCCGGAGCGGCAATACCC-T is Benign according to our data. Variant chr1-240207641-TCCTCCGCCCCCTCTACCCGGAGCGGCAATACCC-T is described in ClinVar as Likely_benign. ClinVar VariationId is 446013.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00774 (358/46266) while in subpopulation AFR AF = 0.0154 (146/9494). AF 95% confidence interval is 0.0133. There are 0 homozygotes in GnomAd4. There are 160 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
FMN2	NM_020066.5	MANE Select	c.2844_2876delACCCGGAGCGGCAATACCCCCTCCGCCCCCTCT	p.Pro949_Leu959del	disruptive_inframe_deletion	Exon 5 of 18	NP_064450.3
FMN2	NM_001305424.2		c.2856_2888delACCCGGAGCGGCAATACCCCCTCCGCCCCCTCT	p.Pro953_Leu963del	disruptive_inframe_deletion	Exon 6 of 19	NP_001292353.1
FMN2	NM_001348094.2		c.1986+19394_1986+19426delACCCGGAGCGGCAATACCCCCTCCGCCCCCTCT		intron	N/A	NP_001335023.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
FMN2	ENST00000319653.14	TSL:5 MANE Select	c.2844_2876delACCCGGAGCGGCAATACCCCCTCCGCCCCCTCT	p.Pro949_Leu959del	disruptive_inframe_deletion	Exon 5 of 18	ENSP00000318884.9
FMN2	ENST00000679980.1		c.188+664_188+696delACCCGGAGCGGCAATACCCCCTCCGCCCCCTCT		intron	N/A	ENSP00000505449.1
FMN2	ENST00000681210.1		c.285+19394_285+19426delACCCGGAGCGGCAATACCCCCTCCGCCCCCTCT		intron	N/A	ENSP00000505131.1

Frequencies

GnomAD3 genomes

AF:

0.00774

AC:

358

AN:

46244

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0154

Gnomad AMI

AF:

0.0510

Gnomad AMR

AF:

0.0107

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000312

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00576

Gnomad OTH

AF:

0.0100

GnomAD2 exomes

AF:

0.00242

AC:

530

AN:

219330

AF XY:

0.00235

show subpopulations

Gnomad AFR exome

AF:

0.00535

Gnomad AMR exome

AF:

0.00344

Gnomad ASJ exome

AF:

0.000120

Gnomad EAS exome

AF:

0.000253

Gnomad FIN exome

AF:

0.000206

Gnomad NFE exome

AF:

0.00305

Gnomad OTH exome

AF:

0.00559

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00445

AC:

3844

AN:

863656

Hom.:

AF XY:

0.00430

AC XY:

1833

AN XY:

426264

show subpopulations

African (AFR)

AF:

0.00843

AC:

124

AN:

14718

American (AMR)

AF:

0.00505

AC:

147

AN:

29114

Ashkenazi Jewish (ASJ)

AF:

0.000646

AC:

AN:

10842

East Asian (EAS)

AF:

0.000422

AC:

AN:

18952

South Asian (SAS)

AF:

0.000536

AC:

AN:

46620

European-Finnish (FIN)

AF:

0.000309

AC:

AN:

32330

Middle Eastern (MID)

AF:

0.00292

AC:

AN:

2056

European-Non Finnish (NFE)

AF:

0.00499

AC:

3377

AN:

676754

Other (OTH)

AF:

0.00434

AC:

140

AN:

32270

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.459

Heterozygous variant carriers

163

325

488

650

813

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

134

268

402

536

670

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00774

AC:

358

AN:

46266

Hom.:

Cov.:

AF XY:

0.00726

AC XY:

160

AN XY:

22044

show subpopulations

African (AFR)

AF:

0.0154

AC:

146

AN:

9494

American (AMR)

AF:

0.0107

AC:

AN:

4494

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

934

East Asian (EAS)

AF:

0.00

AC:

AN:

1364

South Asian (SAS)

AF:

0.00

AC:

AN:

1318

European-Finnish (FIN)

AF:

0.000312

AC:

AN:

3202

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.00576

AC:

141

AN:

24484

Other (OTH)

AF:

0.0100

AC:

AN:

598

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000506

Hom.:

ClinVar

ClinVar submissions as Germline

Significance:Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Intellectual disability, autosomal recessive 47 (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

2.8

Mutation Taster

=188/12

polymorphism

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over