17-17221564-T-C

Variant names:

• chr17-17221564-T-C
• rs876658621
• NM_144997.7:c.844A>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1 PM2

The NM_144997.7(FLCN):​c.844A>G​(p.Thr282Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. T282I) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FLCN NM_144997.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.34
• Publications: 0 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, Labcorp Genetics (formerly Invitae), Orphanet, ClinGen
• 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: Genomics England PanelApp, Orphanet, Ambry Genetics
• 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: Uncertain_significance. The variant received 4 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 26 uncertain in NM_144997.7
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FLCN	NM_144997.7	c.844A>G	p.Thr282Ala	missense_variant	Exon 8 of 14	ENST00000285071.9	NP_659434.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FLCN	ENST00000285071.9	c.844A>G	p.Thr282Ala	missense_variant	Exon 8 of 14	1	NM_144997.7	ENSP00000285071.4
ENSG00000264187	ENST00000427497.3	n.149-2510A>G		intron_variant	Intron 4 of 11	1		ENSP00000394249.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Benign	21
DANN	Benign	0.93
DEOGEN2	Benign	0.18	T;.
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.81	T;T
M_CAP	Uncertain	0.11	D
MetaRNN	Uncertain	0.57	D;D
MetaSVM	Uncertain	0.53	D
MutationAssessor	Benign	1.8	L;L
PhyloP100		7.3
PrimateAI	Uncertain	0.79	T
PROVEAN	Benign	-0.55	N;N
REVEL	Uncertain	0.52
Sift	Benign	0.53	T;T
Sift4G	Benign	0.33	T;T
Polyphen		0.073	B;D
Vest4		0.90
MutPred		0.21		Loss of phosphorylation at T282 (P = 0.0227);Loss of phosphorylation at T282 (P = 0.0227);
MVP		0.70
MPC		0.37
ClinPred		0.90	D
GERP RS		6.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.25
gMVP		0.47

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: rs876658621; hg19: chr17-17124878;