rs41442248

Positions:

• chr17-17214864-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_144997.7(FLCN):​c.1538+121C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0249 in 1,072,898 control chromosomes in the GnomAD database, including 461 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.023 (76 hom., cov: 32)
  • Exomes 𝑓: 0.025 (385 hom.)
• Consequence: FLCN NM_144997.7 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.87

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

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BP6: Variant 17-17214864-G-A is Benign according to our data. Variant chr17-17214864-G-A is described in ClinVar as [Benign]. Clinvar id is 1292853.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-17214864-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0231 (3521/152124) while in subpopulation NFE AF= 0.0274 (1863/67994). AF 95% confidence interval is 0.0264. There are 76 homozygotes in gnomad4. There are 1809 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 3521 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FLCN	NM_144997.7	c.1538+121C>T		intron_variant		ENST00000285071.9	NP_659434.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FLCN	ENST00000285071.9	c.1538+121C>T		intron_variant		1	NM_144997.7	ENSP00000285071.4
ENSG00000264187	ENST00000427497.3	n.*372+121C>T		intron_variant		1		ENSP00000394249.3
MPRIP	ENST00000578209.5	c.*18-2626G>A		intron_variant		3		ENSP00000464276.1

Frequencies

GnomAD3 genomes AF: 0.0232 AC: 3525 AN: 152006 Hom.: 76 Cov.: 32

Gnomad AFR AF: 0.00527

Gnomad AMI AF: 0.0395

Gnomad AMR AF: 0.0257

Gnomad ASJ AF: 0.0326

Gnomad EAS AF: 0.000387

Gnomad SAS AF: 0.0151

Gnomad FIN AF: 0.0723

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0274

Gnomad OTH AF: 0.0220

GnomAD4 exome AF: 0.0252 AC: 23247 AN: 920774 Hom.: 385 AF XY: 0.0252 AC XY: 12015 AN XY: 476590

Gnomad4 AFR exome AF: 0.00533

Gnomad4 AMR exome AF: 0.0164

Gnomad4 ASJ exome AF: 0.0351

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0174

Gnomad4 FIN exome AF: 0.0628

Gnomad4 NFE exome AF: 0.0258

Gnomad4 OTH exome AF: 0.0279

GnomAD4 genome AF: 0.0231 AC: 3521 AN: 152124 Hom.: 76 Cov.: 32 AF XY: 0.0243 AC XY: 1809 AN XY: 74388

Gnomad4 AFR AF: 0.00528

Gnomad4 AMR AF: 0.0257

Gnomad4 ASJ AF: 0.0326

Gnomad4 EAS AF: 0.000388

Gnomad4 SAS AF: 0.0153

Gnomad4 FIN AF: 0.0723

Gnomad4 NFE AF: 0.0274

Gnomad4 OTH AF: 0.0218

Alfa AF: 0.0279 Hom.: 8

Bravo AF: 0.0195

Asia WGS AF: 0.00693 AC: 24 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 26, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.012
DANN	Benign	0.67

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

Publications

LitVar

Other links and lift over

dbSNP: rs41442248; hg19: chr17-17118178;