17-17223987-A-T

Position:

• chr17-17223987-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_144997.7(FLCN):​c.553T>A​(p.Ser185Thr) 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.

• Frequency: Genomes: not found (cov: 33)
• Consequence: FLCN NM_144997.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.68

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]

ENSG00000264187 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a domain uDENN FLCN/SMCR8-type (size 156) in uniprot entity FLCN_HUMAN there are 14 pathogenic changes around while only 2 benign (88%) in NM_144997.7
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FLCN	NM_144997.7	c.553T>A	p.Ser185Thr	missense_variant	6/14	ENST00000285071.9	NP_659434.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FLCN	ENST00000285071.9	c.553T>A	p.Ser185Thr	missense_variant	6/14	1	NM_144997.7	ENSP00000285071.4
ENSG00000264187	ENST00000427497.3	n.148+4003T>A		intron_variant		1		ENSP00000394249.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.69
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.49	T;.;T
Eigen	Uncertain	0.63
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D;D;D
M_CAP	Uncertain	0.18	D
MetaRNN	Uncertain	0.61	D;D;D
MetaSVM	Uncertain	0.26	D
MutationAssessor	Benign	1.0	L;L;.
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-1.0	N;N;N
REVEL	Uncertain	0.54
Sift	Uncertain	0.013	D;T;T
Sift4G	Uncertain	0.044	D;T;T
Polyphen		1.0	D;D;.
Vest4		0.75
MutPred		0.44		Gain of helix (P = 0.132);Gain of helix (P = 0.132);.;
MVP		0.55
MPC		0.66
ClinPred		0.86	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.81
gMVP		0.76

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

Publications

LitVar

Other links and lift over

dbSNP: rs876657646; hg19: chr17-17127301;