rs4985751

Positions:

• chr17-17217299-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.1063-117C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00913 in 765,972 control chromosomes in the GnomAD database, including 98 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0089 (18 hom., cov: 33)
  • Exomes 𝑓: 0.0092 (80 hom.)
• Consequence: FLCN NM_144997.7 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.982

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=-0.89).
• BP6: Variant 17-17217299-G-A is Benign according to our data. Variant chr17-17217299-G-A is described in ClinVar as [Benign]. Clinvar id is 1238435.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-17217299-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00894 (1362/152336) while in subpopulation AMR AF= 0.0349 (534/15302). AF 95% confidence interval is 0.0325. There are 18 homozygotes in gnomad4. There are 647 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1362 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FLCN	NM_144997.7	c.1063-117C>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.1063-117C>T		intron_variant		1	NM_144997.7	ENSP00000285071.4
ENSG00000264187	ENST00000427497.3	n.185-117C>T		intron_variant		1		ENSP00000394249.3
MPRIP	ENST00000578209.5	c.*18-191G>A		intron_variant		3		ENSP00000464276.1
FLCN	ENST00000577591.1	n.86-117C>T		intron_variant		2

Frequencies

GnomAD3 genomes AF: 0.00892 AC: 1358 AN: 152218 Hom.: 18 Cov.: 33

Gnomad AFR AF: 0.00292

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0347

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.0235

Gnomad SAS AF: 0.00311

Gnomad FIN AF: 0.00301

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00770

Gnomad OTH AF: 0.00574

GnomAD4 exome AF: 0.00918 AC: 5635 AN: 613636 Hom.: 80 AF XY: 0.00832 AC XY: 2731 AN XY: 328244

Gnomad4 AFR exome AF: 0.00327

Gnomad4 AMR exome AF: 0.0500

Gnomad4 ASJ exome AF: 0.000935

Gnomad4 EAS exome AF: 0.0138

Gnomad4 SAS exome AF: 0.00158

Gnomad4 FIN exome AF: 0.00408

Gnomad4 NFE exome AF: 0.00766

Gnomad4 OTH exome AF: 0.00837

GnomAD4 genome AF: 0.00894 AC: 1362 AN: 152336 Hom.: 18 Cov.: 33 AF XY: 0.00869 AC XY: 647 AN XY: 74496

Gnomad4 AFR AF: 0.00291

Gnomad4 AMR AF: 0.0349

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.0235

Gnomad4 SAS AF: 0.00311

Gnomad4 FIN AF: 0.00301

Gnomad4 NFE AF: 0.00770

Gnomad4 OTH AF: 0.00568

Alfa AF: 0.00667 Hom.: 0

Bravo AF: 0.0113

Asia WGS AF: 0.0100 AC: 35 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	-0.89
CADD	Benign	2.5
DANN	Benign	0.65

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: rs4985751; hg19: chr17-17120613;