rs143483053

Variant names:

• chr17-17219122-C-T
• rs143483053
• NM_144997.7:c.959G>A

Your query was ambiguous. Multiple possible variants found:

• chr17-17219122-C-T
• chr17-17219122-C-A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_144997.7(FLCN):​c.959G>A​(p.Arg320Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00102 in 1,614,080 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R320W) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00068 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0011 (2 hom.)
• Consequence: FLCN NM_144997.7 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:16 O:1
• Conservation: PhyloP100: 1.09
• Publications: 11 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, ClinGen, Orphanet, Labcorp Genetics (formerly Invitae)
• 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: Orphanet, Ambry Genetics, Genomics England PanelApp
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.01630044).
• BP6: Variant 17-17219122-C-T is Benign according to our data. Variant chr17-17219122-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 41863.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000683 (104/152208) while in subpopulation NFE AF = 0.00113 (77/68034). AF 95% confidence interval is 0.000928. There are 0 homozygotes in GnomAd4. There are 45 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 104 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_144997.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLCN	NM_144997.7	MANE Select	c.959G>A	p.Arg320Gln	missense	Exon 9 of 14	NP_659434.2
	FLCN	NM_001353229.2		c.1013G>A	p.Arg338Gln	missense	Exon 11 of 16	NP_001340158.1
	FLCN	NM_001353230.2		c.959G>A	p.Arg320Gln	missense	Exon 10 of 15	NP_001340159.1	Q8NFG4-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLCN	ENST00000285071.9	TSL:1 MANE Select	c.959G>A	p.Arg320Gln	missense	Exon 9 of 14	ENSP00000285071.4	Q8NFG4-1
	ENSG00000264187	ENST00000427497.3	TSL:1	n.149-68G>A		intron	N/A	ENSP00000394249.3	J3QW42
	FLCN	ENST00000962729.1		c.1064G>A	p.Arg355Gln	missense	Exon 11 of 16	ENSP00000632788.1

Frequencies

GnomAD3 genomes AF: 0.000683 AC: 104 AN: 152208 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000289

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00113

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00113

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000811 AC: 204 AN: 251472 AF XY: 0.000706

Gnomad AFR exome AF: 0.000431

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00106

Gnomad NFE exome AF: 0.00149

Gnomad OTH exome AF: 0.000652

GnomAD4 exome AF: 0.00105 AC: 1536 AN: 1461872 Hom.: 2 Cov.: 35 AF XY: 0.00106 AC XY: 769 AN XY: 727244

African (AFR) AF: 0.000388 AC: 13 AN: 33480

American (AMR) AF: 0.0000447 AC: 2 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86258

European-Finnish (FIN) AF: 0.00150 AC: 80 AN: 53404

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5766

European-Non Finnish (NFE) AF: 0.00127 AC: 1411 AN: 1112008

Other (OTH) AF: 0.000447 AC: 27 AN: 60396

GnomAD4 genome AF: 0.000683 AC: 104 AN: 152208 Hom.: 0 Cov.: 31 AF XY: 0.000605 AC XY: 45 AN XY: 74350

African (AFR) AF: 0.000289 AC: 12 AN: 41458

American (AMR) AF: 0.000131 AC: 2 AN: 15284

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00113 AC: 12 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00113 AC: 77 AN: 68034

Other (OTH) AF: 0.000478 AC: 1 AN: 2094

Alfa AF: 0.00108 Hom.: 0

Bravo AF: 0.000661

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00163 AC: 14

ExAC AF: 0.000782 AC: 95

EpiCase AF: 0.000872

EpiControl AF: 0.00124

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	6	not provided (7)
-	-	3	Birt-Hogg-Dube syndrome (3)
-	-	3	not specified (4)
-	-	2	Hereditary cancer-predisposing syndrome (2)
-	-	1	Familial spontaneous pneumothorax (1)
-	-	1	FLCN-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	15
DANN	Benign	0.88
DEOGEN2	Benign	0.20	T
Eigen	Benign	-0.79
Eigen_PC	Benign	-0.61
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.042	D
MetaRNN	Benign	0.016	T
MetaSVM	Benign	-0.58	T
MutationAssessor	Benign	0.67	N
PhyloP100		1.1
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.49	N
REVEL	Benign	0.22
Sift	Benign	0.23	T
Sift4G	Benign	0.43	T
Polyphen		0.0020	B
Vest4		0.16
MVP		0.20
MPC		0.43
ClinPred		0.013	T
GERP RS		2.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.020
gMVP		0.12
Mutation Taster		=94/6	polymorphism

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: rs143483053; hg19: chr17-17122436;