rs876657646

Variant names:

• chr17-17223987-A-G
• rs876657646
• NM_144997.7:c.553T>C

Your query was ambiguous. Multiple possible variants found:

• chr17-17223987-A-G
• chr17-17223987-A-T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1 PM2 PP3 PP5

The NM_144997.7(FLCN):​c.553T>C​(p.Ser185Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S185F) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: FLCN NM_144997.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 8.68
• Publications: 4 publications found

Genes affected

FLCN (HGNC:27310): (folliculin) This gene is located within the Smith-Magenis syndrome region on chromosome 17. Mutations in this gene are associated with Birt-Hogg-Dube syndrome, which is characterized by fibrofolliculomas, renal tumors, lung cysts, and pneumothorax. Alternative splicing of this gene results in two transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008]

FLCN Gene-Disease associations (from GenCC):

• Birt-Hogg-Dube syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, ClinGen, Orphanet, Labcorp Genetics (formerly Invitae)
• Birt-Hogg-Dube syndrome 1

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P, Ambry Genetics
• familial spontaneous pneumothorax

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, Genomics England PanelApp
• renal carcinoma

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• colorectal cancer

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ENSG00000264187 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 30 uncertain in NM_144997.7
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.822
• PP5: Variant 17-17223987-A-G is Pathogenic according to our data. Variant chr17-17223987-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 228263.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_144997.7. 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
	FLCN	NM_144997.7	MANE Select	c.553T>C	p.Ser185Pro	missense	Exon 6 of 14	NP_659434.2
	FLCN	NM_001353229.2		c.607T>C	p.Ser203Pro	missense	Exon 8 of 16	NP_001340158.1
	FLCN	NM_001353230.2		c.553T>C	p.Ser185Pro	missense	Exon 7 of 15	NP_001340159.1	Q8NFG4-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLCN	ENST00000285071.9	TSL:1 MANE Select	c.553T>C	p.Ser185Pro	missense	Exon 6 of 14	ENSP00000285071.4	Q8NFG4-1
	FLCN	ENST00000389169.9	TSL:1	c.553T>C	p.Ser185Pro	missense	Exon 6 of 8	ENSP00000373821.5	Q8NFG4-2
	ENSG00000264187	ENST00000427497.3	TSL:1	n.148+4003T>C		intron	N/A	ENSP00000394249.3	J3QW42

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	1	-	Birt-Hogg-Dube syndrome (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.84	D
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D
M_CAP	Pathogenic	0.43	D
MetaRNN	Pathogenic	0.82	D
MetaSVM	Uncertain	0.65	D
MutationAssessor	Benign	1.9	L
PhyloP100		8.7
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-2.9	D
REVEL	Pathogenic	0.84
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.037	D
Polyphen		1.0	D
Vest4		0.99
MutPred		0.55		Loss of helix (P = 0.028)
MVP		0.84
MPC		1.1
ClinPred		0.97	D
GERP RS		5.7
Varity_R		0.98
gMVP		0.95
Mutation Taster		=5/95	disease causing (ClinVar)

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: rs876657646; hg19: chr17-17127301;