rs41323249

Variant names:

• chr17-17220853-C-T
• rs41323249
• NM_144997.7:c.871+684G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_144997.7(FLCN):​c.871+684G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.157 in 224,338 control chromosomes in the GnomAD database, including 3,124 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 0.17 (2346 hom., cov: 32)
  • Exomes 𝑓: 0.13 (778 hom.)
• Consequence: FLCN NM_144997.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.366
• Publications: 5 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=-0.91).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.218 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FLCN	NM_144997.7	c.871+684G>A		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	ENST00000285071.9	c.871+684G>A		intron_variant	Intron 8 of 13	1	NM_144997.7	ENSP00000285071.4
ENSG00000264187	ENST00000427497.3	n.149-1799G>A		intron_variant	Intron 4 of 11	1		ENSP00000394249.3
FLCN	ENST00000466317.1	n.1398G>A		non_coding_transcript_exon_variant	Exon 2 of 2	2

Frequencies

GnomAD3 genomes AF: 0.171 AC: 25992 AN: 152016 Hom.: 2342 Cov.: 32

Gnomad AFR AF: 0.222

Gnomad AMI AF: 0.160

Gnomad AMR AF: 0.160

Gnomad ASJ AF: 0.188

Gnomad EAS AF: 0.00462

Gnomad SAS AF: 0.128

Gnomad FIN AF: 0.119

Gnomad MID AF: 0.253

Gnomad NFE AF: 0.165

Gnomad OTH AF: 0.189

GnomAD4 exome AF: 0.128 AC: 9258 AN: 72204 Hom.: 778 Cov.: 0 AF XY: 0.127 AC XY: 4783 AN XY: 37582

African (AFR) AF: 0.186 AC: 264 AN: 1418

American (AMR) AF: 0.153 AC: 561 AN: 3674

Ashkenazi Jewish (ASJ) AF: 0.175 AC: 302 AN: 1722

East Asian (EAS) AF: 0.00565 AC: 24 AN: 4250

South Asian (SAS) AF: 0.116 AC: 1220 AN: 10482

European-Finnish (FIN) AF: 0.0889 AC: 293 AN: 3294

Middle Eastern (MID) AF: 0.223 AC: 59 AN: 264

European-Non Finnish (NFE) AF: 0.138 AC: 5974 AN: 43240

Other (OTH) AF: 0.145 AC: 561 AN: 3860

GnomAD4 genome AF: 0.171 AC: 26018 AN: 152134 Hom.: 2346 Cov.: 32 AF XY: 0.169 AC XY: 12582 AN XY: 74384

African (AFR) AF: 0.222 AC: 9195 AN: 41494

American (AMR) AF: 0.160 AC: 2442 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.188 AC: 652 AN: 3466

East Asian (EAS) AF: 0.00463 AC: 24 AN: 5186

South Asian (SAS) AF: 0.129 AC: 620 AN: 4812

European-Finnish (FIN) AF: 0.119 AC: 1263 AN: 10576

Middle Eastern (MID) AF: 0.255 AC: 75 AN: 294

European-Non Finnish (NFE) AF: 0.165 AC: 11205 AN: 68000

Other (OTH) AF: 0.188 AC: 396 AN: 2112

Alfa AF: 0.173 Hom.: 491

Bravo AF: 0.176

Asia WGS AF: 0.0750 AC: 261 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	1.3
DANN	Benign	0.50
PhyloP100		0.37
Mutation Taster		=100/0	polymorphism (auto)

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: rs41323249; hg19: chr17-17124167;