chr17-17219212-G-A

Variant names:

• chr17-17219212-G-A
• rs1555608676
• NM_144997.7:c.872-3C>T

GermlineCancer (beta)

Variant summary

Our verdict is Likely benign.

-4 Likely Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -4 classification points (ACMG Germline Pathogenicity v2019). PM2BP4_ModerateBP6_Strong

The NM_144997.7(FLCN):c.872-3C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign/Likely Benign (★★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: FLCN NM_144997.7 splice_region, intron
• Scores: Splicing: ADA: 0.005930
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.538
• Publications: 0 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: Orphanet, Genomics England PanelApp, ClinGen, Labcorp Genetics (formerly Invitae)
• Birt-Hogg-Dube syndrome 1

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P, Ambry Genetics
• Birt-Hogg-Dube syndrome

  Inheritance: AD Classification: STRONG Submitted by: PanelApp Australia
• 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:):

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Likely_benign. The variant received -4 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		Absent from gnomAD (AD/XL gene) — PM2; Absent from gnomAD at well-covered site (MOI: AD/XL) (threshold 0.0001) — PM2 moderate.
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Moderate).
	BP6Reputable source reports benign		ClinVar 2-star benign — strong (BP6); ClinVar germline classification: Benign/Likely Benign, 2 star(s).

Variant Effect in Transcripts

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

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	FLCN NM_144997.7	MANE Select	c.872-3C>T	splice_regionintron	Intron 8 of 13	Prot: NP_659434.2
	FLCN NM_001353229.2		c.926-3C>T	splice_regionintron	Intron 10 of 15	Prot: NP_001340158.1
	FLCN NM_001353230.2		c.872-3C>T	splice_regionintron	Intron 9 of 14	Prot: NP_001340159.1 UniProt:

FLCN NM_144997.7

MANE Select

HGVSc / HGVSpc.872-3C>T

Exon rankIntron 8 of 13

splice_regionintron

Prot: NP_659434.2

FLCN NM_001353229.2

HGVSc / HGVSpc.926-3C>T

Exon rankIntron 10 of 15

splice_regionintron

Prot: NP_001340158.1

FLCN NM_001353230.2

HGVSc / HGVSpc.872-3C>T

Exon rankIntron 9 of 14

splice_regionintron

Prot: NP_001340159.1UniProt: Q8NFG4-1

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	FLCN ENST00000285071.9	TSL:1MANE Select	c.872-3C>T	splice_regionintron	Intron 8 of 13	Prot: ENSP00000285071.4 UniProt:
	ENSG00000264187 ENST00000427497.3	TSL:1	n.149-158C>T	intron	Intron 4 of 11	Prot: ENSP00000394249.3 UniProt:
	FLCN ENST00000962729.1		c.977-3C>T	splice_regionintron	Intron 10 of 15	Prot: ENSP00000632788.1 UniProt:

FLCN ENST00000285071.9

TSL:1MANE Select

HGVSc / HGVSpc.872-3C>T

Exon rankIntron 8 of 13

splice_regionintron

Prot: ENSP00000285071.4UniProt: Q8NFG4-1

ENSG00000264187 ENST00000427497.3

TSL:1

HGVSc / HGVSpn.149-158C>T

Exon rankIntron 4 of 11

intron

Prot: ENSP00000394249.3UniProt: J3QW42

FLCN ENST00000962729.1

HGVSc / HGVSpc.977-3C>T

Exon rankIntron 10 of 15

splice_regionintron

Prot: ENSP00000632788.1UniProt: A0ACI8V6X7

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 5 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:31
GnomAD4 exome	AF:	AC:	Hom:	AN:	Cov:35
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:31
TOPMed (Bravo)	AF: 0.00000756	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.00	AC:0	Hom:0	AN:13470	Cov:

Showing 5 sources

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Birt-Hogg-Dube syndrome (1)
-	-	1	Hereditary cancer-predisposing syndrome (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Uncertain	13
BayesDel_noAF	Benign	-0.39
CADD	Benign	12
DANN	Benign	0.76
GPN-Star LLR	N/A	-2.4
GPN-Star score	N/A	2.4
PhyloP100	Benign	0.54
RBP_binding_hub_radar	N/A	0.0
RBP_regulation_power_radar	N/A	1.1

Showing 9 of 9 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
dbscSNV1_ADA	Benign	0.0059
dbscSNV1_RF	Benign	0.040
Pangolin (max)	Benign	0.020
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 4 of 4 scores

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs1555608676;

hg19: chr17-17122526;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar