rs1033129279

Variant names:

• chr17-17217061-G-A
• rs1033129279
• NM_144997.7:c.1176+8C>T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_144997.7(FLCN):​c.1176+8C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000069 in 1,593,802 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: FLCN NM_144997.7 splice_region, intron
• Scores: Splicing: ADA: 0.0001424
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0290
• 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]

ENSG00000264187 (HGNC:):

MPRIP (HGNC:30321): (myosin phosphatase Rho interacting protein) Enables cadherin binding activity. Predicted to be involved in actin filament organization. Located in actin cytoskeleton and cytosol. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 17-17217061-G-A is Benign according to our data. Variant chr17-17217061-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 415625.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAdExome4 at 9 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.1176+8C>T		splice_region intron	N/A	NP_659434.2
	FLCN	NM_001353229.2		c.1230+8C>T		splice_region intron	N/A	NP_001340158.1
	FLCN	NM_001353230.2		c.1176+8C>T		splice_region intron	N/A	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.1176+8C>T		splice_region intron	N/A	ENSP00000285071.4	Q8NFG4-1
	ENSG00000264187	ENST00000427497.3	TSL:1	n.*10+8C>T		splice_region intron	N/A	ENSP00000394249.3	J3QW42
	FLCN	ENST00000962729.1		c.1281+8C>T		splice_region intron	N/A	ENSP00000632788.1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152198 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000624 AC: 9 AN: 1441604 Hom.: 0 Cov.: 28 AF XY: 0.0000111 AC XY: 8 AN XY: 718866

African (AFR) AF: 0.00 AC: 0 AN: 33056

American (AMR) AF: 0.00 AC: 0 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25974

East Asian (EAS) AF: 0.00 AC: 0 AN: 39608

South Asian (SAS) AF: 0.00 AC: 0 AN: 85830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53300

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5734

European-Non Finnish (NFE) AF: 0.00000823 AC: 9 AN: 1093694

Other (OTH) AF: 0.00 AC: 0 AN: 59718

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152198 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74368

African (AFR) AF: 0.00 AC: 0 AN: 41456

American (AMR) AF: 0.00 AC: 0 AN: 15286

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68040

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.55
DANN	Benign	0.88
PhyloP100		-0.029

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00014
dbscSNV1_RF	Benign	0.0020
SpliceAI score (max)		0.010		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: rs1033129279; hg19: chr17-17120375;