Genetic Variant FLOT1:p.Arg190Pro (chr6-30740497-C-G) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_005803.4(FLOT1):c.569G>C(p.Arg190Pro) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,130 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R190W) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

FLOT1
NM_005803.4 missense, splice_region

Scores

Splicing: ADA: 0.9730

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.844

Publications

1 publications found

Variant links:

Genes affected

FLOT1 (HGNC:3757): (flotillin 1) This gene encodes an protein that localizes to the caveolae, which are small domains on the inner cell membranes. This protein plays a role in vesicle trafficking and cell morphology. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2016]

FLOT1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.781

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005803.4. 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
	FLOT1	NM_005803.4	MANE Select	c.569G>C	p.Arg190Pro	missense splice_region	Exon 7 of 13	NP_005794.1	Q5ST80
	FLOT1	NM_001318875.2		c.425G>C	p.Arg142Pro	missense splice_region	Exon 6 of 12	NP_001305804.1	O75955-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FLOT1	ENST00000376389.8	TSL:1 MANE Select	c.569G>C	p.Arg190Pro	missense splice_region	Exon 7 of 13	ENSP00000365569.3	O75955-1
FLOT1	ENST00000445853.5	TSL:1	c.569G>C	p.Arg190Pro	missense splice_region	Exon 6 of 7	ENSP00000398834.1	A2AB12
FLOT1	ENST00000903950.1		c.674G>C	p.Arg225Pro	missense splice_region	Exon 7 of 13	ENSP00000574009.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000405

AC:

AN:

246668

AF XY:

0.00000744

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460130

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726440

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33466

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86226

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52320

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5346

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111884

Other (OTH)

AF:

0.00

AC:

AN:

60330

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.94

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Pathogenic

0.23

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.81

Eigen

Uncertain

0.44

Eigen_PC

Uncertain

0.42

FATHMM_MKL

Uncertain

0.90

M_CAP

Uncertain

0.14

MetaRNN

Pathogenic

0.78

MetaSVM

Pathogenic

0.99

MutationAssessor

Uncertain

2.7

PhyloP100

0.84

PrimateAI

Uncertain

0.58

PROVEAN

Uncertain

-4.3

REVEL

Uncertain

0.63

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.014

Polyphen

0.86

Vest4

0.51

MutPred

0.49

Loss of MoRF binding (P = 6e-04)

MVP

0.98

MPC

1.9

ClinPred

0.94

GERP RS

3.8

Varity_R

0.84

gMVP

0.94

Mutation Taster

=50/50

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.97

dbscSNV1_RF

Benign

0.72

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over