rs34311146

Positions:

• chr17-17215375-G-A
• chr17-17215375-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000285071.9(FLCN):​c.1301-59C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.17 in 1,610,620 control chromosomes in the GnomAD database, including 25,829 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1718 hom., cov: 32)
  • Exomes 𝑓: 0.17 (24111 hom.)
• Consequence: FLCN ENST00000285071.9 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.99

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]

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=-0.98).
• BP6: Variant 17-17215375-G-A is Benign according to our data. Variant chr17-17215375-G-A is described in ClinVar as [Benign]. Clinvar id is 1259688.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-17215375-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.192 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FLCN	NM_144997.7	c.1301-59C>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.1301-59C>T		intron_variant		1	NM_144997.7	ENSP00000285071	P1
MPRIP	ENST00000578209.5	c.*18-2115G>A		intron_variant		3		ENSP00000464276

Frequencies

GnomAD3 genomes AF: 0.130 AC: 19766 AN: 152030 Hom.: 1722 Cov.: 32

Gnomad AFR AF: 0.0340

Gnomad AMI AF: 0.207

Gnomad AMR AF: 0.134

Gnomad ASJ AF: 0.236

Gnomad EAS AF: 0.00386

Gnomad SAS AF: 0.0874

Gnomad FIN AF: 0.112

Gnomad MID AF: 0.250

Gnomad NFE AF: 0.195

Gnomad OTH AF: 0.175

GnomAD4 exome AF: 0.174 AC: 253530 AN: 1458472 Hom.: 24111 AF XY: 0.172 AC XY: 125057 AN XY: 725598

Gnomad4 AFR exome AF: 0.0306

Gnomad4 AMR exome AF: 0.120

Gnomad4 ASJ exome AF: 0.234

Gnomad4 EAS exome AF: 0.00239

Gnomad4 SAS exome AF: 0.0898

Gnomad4 FIN exome AF: 0.127

Gnomad4 NFE exome AF: 0.194

Gnomad4 OTH exome AF: 0.165

GnomAD4 genome AF: 0.130 AC: 19752 AN: 152148 Hom.: 1718 Cov.: 32 AF XY: 0.123 AC XY: 9174 AN XY: 74380

Gnomad4 AFR AF: 0.0339

Gnomad4 AMR AF: 0.134

Gnomad4 ASJ AF: 0.236

Gnomad4 EAS AF: 0.00387

Gnomad4 SAS AF: 0.0867

Gnomad4 FIN AF: 0.112

Gnomad4 NFE AF: 0.195

Gnomad4 OTH AF: 0.173

Alfa AF: 0.155 Hom.: 282

Bravo AF: 0.129

Asia WGS AF: 0.0400 AC: 140 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	Mar 03, 2015	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.044
DANN	Benign	0.50
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs34311146; hg19: chr17-17118689;