6-30731049-C-G

Variant names:

• chr6-30731049-C-G
• rs149283777
• NM_005803.4:c.775G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_005803.4(FLOT1):​c.775G>C​(p.Val259Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,459,098 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 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. V259M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: FLOT1 NM_005803.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.02
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.350853).

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.775G>C	p.Val259Leu	missense	Exon 9 of 13	NP_005794.1	Q5ST80
	FLOT1	NM_001318875.2		c.631G>C	p.Val211Leu	missense	Exon 8 of 12	NP_001305804.1	O75955-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLOT1	ENST00000376389.8	TSL:1 MANE Select	c.775G>C	p.Val259Leu	missense	Exon 9 of 13	ENSP00000365569.3	O75955-1
	FLOT1	ENST00000903950.1		c.880G>C	p.Val294Leu	missense	Exon 9 of 13	ENSP00000574009.1
	FLOT1	ENST00000914089.1		c.814G>C	p.Val272Leu	missense	Exon 9 of 13	ENSP00000584148.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459098 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 725950

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50878

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5736

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111840

Other (OTH) AF: 0.00 AC: 0 AN: 60374

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.54
BayesDel_addAF	Benign	-0.041	T
BayesDel_noAF	Benign	-0.30
CADD	Uncertain	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.36	T
Eigen	Benign	0.16
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Benign	0.0092	T
MetaRNN	Benign	0.35	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		6.0
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.20
Sift	Benign	0.10	T
Sift4G	Benign	0.21	T
Polyphen		0.0060	B
Vest4		0.41
MutPred		0.39		Gain of MoRF binding (P = 0.138)
MVP		0.49
MPC		1.0
ClinPred		0.86	D
GERP RS		4.2
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.8
Varity_R		0.12
gMVP		0.76
Mutation Taster		=60/40	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: rs149283777; hg19: chr6-30698826;