17-17221333-T-C

Variant names:

• chr17-17221333-T-C
• rs41462849
• ENST00000389169.9:c.*46A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The ENST00000389169.9(FLCN):​c.*46A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00302 in 1,563,416 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0018 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0031 (9 hom.)
• Consequence: FLCN ENST00000389169.9 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.58
• Publications: 3 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0018 (274/152242) while in subpopulation NFE AF = 0.00353 (240/68008). AF 95% confidence interval is 0.00316. There are 1 homozygotes in GnomAd4. There are 116 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 274 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FLCN	NM_144997.7	c.871+204A>G		intron_variant	Intron 8 of 13	ENST00000285071.9	NP_659434.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FLCN	ENST00000389169.9	c.*46A>G		3_prime_UTR_variant	Exon 8 of 8	1		ENSP00000373821.5
FLCN	ENST00000285071.9	c.871+204A>G		intron_variant	Intron 8 of 13	1	NM_144997.7	ENSP00000285071.4
ENSG00000264187	ENST00000427497.3	n.149-2279A>G		intron_variant	Intron 4 of 11	1		ENSP00000394249.3
FLCN	ENST00000466317.1	n.918A>G		non_coding_transcript_exon_variant	Exon 2 of 2	2

Frequencies

GnomAD3 genomes AF: 0.00180 AC: 274 AN: 152124 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000628

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00353

Gnomad OTH AF: 0.000955

GnomAD2 exomes AF: 0.00162 AC: 279 AN: 172538 AF XY: 0.00145

Gnomad AFR exome AF: 0.000406

Gnomad AMR exome AF: 0.000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00353

Gnomad OTH exome AF: 0.00191

GnomAD4 exome AF: 0.00315 AC: 4441 AN: 1411174 Hom.: 9 Cov.: 31 AF XY: 0.00303 AC XY: 2115 AN XY: 697574

African (AFR) AF: 0.000532 AC: 17 AN: 31934

American (AMR) AF: 0.000737 AC: 27 AN: 36648

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25282

East Asian (EAS) AF: 0.0000276 AC: 1 AN: 36220

South Asian (SAS) AF: 0.0000372 AC: 3 AN: 80652

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50084

Middle Eastern (MID) AF: 0.000525 AC: 3 AN: 5712

European-Non Finnish (NFE) AF: 0.00383 AC: 4160 AN: 1086098

Other (OTH) AF: 0.00393 AC: 230 AN: 58544

GnomAD4 genome AF: 0.00180 AC: 274 AN: 152242 Hom.: 1 Cov.: 32 AF XY: 0.00156 AC XY: 116 AN XY: 74426

African (AFR) AF: 0.000626 AC: 26 AN: 41544

American (AMR) AF: 0.000327 AC: 5 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00353 AC: 240 AN: 68008

Other (OTH) AF: 0.000945 AC: 2 AN: 2116

Alfa AF: 0.00248 Hom.: 0

Bravo AF: 0.00191

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.45
DANN	Benign	0.21
PhyloP100		-1.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs41462849; hg19: chr17-17124647;