17-17228041-C-T

Position:

• chr17-17228041-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The ENST00000285071.9(FLCN):​c.97G>A​(p.Asp33Asn) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict 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. D33E) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: FLCN ENST00000285071.9 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.57

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.31193414).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FLCN	NM_144997.7	c.97G>A	p.Asp33Asn	missense_variant	4/14	ENST00000285071.9	NP_659434.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FLCN	ENST00000285071.9	c.97G>A	p.Asp33Asn	missense_variant	4/14	1	NM_144997.7	ENSP00000285071	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.037	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.13	T;.;.
Eigen	Benign	-0.067
Eigen_PC	Benign	0.13
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.86	D;D;T
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.31	T;T;T
MetaSVM	Benign	-0.33	T
MutationAssessor	Benign	0.0	N;N;.
MutationTaster	Benign	0.93	N;N
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.48	N;N;.
REVEL	Uncertain	0.36
Sift	Benign	0.078	T;T;.
Sift4G	Benign	0.34	T;T;.
Polyphen		0.0030	B;B;.
Vest4		0.19
MutPred		0.21		Gain of catalytic residue at D33 (P = 0.152);Gain of catalytic residue at D33 (P = 0.152);Gain of catalytic residue at D33 (P = 0.152);
MVP		0.53
MPC		0.36
ClinPred		0.77	D
GERP RS		5.5
Varity_R		0.057
gMVP		0.21

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-17131355;