17-17212252-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_144997.7(FLCN):c.*1403T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.716 in 170,342 control chromosomes in the GnomAD database, including 44,076 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.72 (39508 hom., cov: 30)
  • Exomes 𝑓: 0.70 (4568 hom.)
• Consequence: FLCN NM_144997.7 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: -0.0630

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 17-17212252-A-G is Benign according to our data. Variant chr17-17212252-A-G is described in ClinVar as [Benign]. Clinvar id is 322033.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.734 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FLCN	NM_144997.7	c.*1403T>C		3_prime_UTR_variant	14/14	ENST00000285071.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLCN	ENST00000285071.9	c.*1403T>C		3_prime_UTR_variant	14/14	1	NM_144997.7	P1
MPRIP	ENST00000578209.5	c.*18-5238A>G		intron_variant		3

Frequencies

GnomAD3 genomes AF: 0.719 AC: 109042 AN: 151748 Hom.: 39501 Cov.: 30

Gnomad AFR AF: 0.660

Gnomad AMI AF: 0.849

Gnomad AMR AF: 0.704

Gnomad ASJ AF: 0.698

Gnomad EAS AF: 0.725

Gnomad SAS AF: 0.667

Gnomad FIN AF: 0.857

Gnomad MID AF: 0.620

Gnomad NFE AF: 0.740

Gnomad OTH AF: 0.701

GnomAD4 exome AF: 0.701 AC: 12948 AN: 18476 Hom.: 4568 Cov.: 0 AF XY: 0.697 AC XY: 5866 AN XY: 8418

Gnomad4 AFR exome AF: 0.636

Gnomad4 AMR exome AF: 0.679

Gnomad4 ASJ exome AF: 0.686

Gnomad4 EAS exome AF: 0.678

Gnomad4 SAS exome AF: 0.681

Gnomad4 FIN exome AF: 0.857

Gnomad4 NFE exome AF: 0.717

Gnomad4 OTH exome AF: 0.704

GnomAD4 genome AF: 0.718 AC: 109094 AN: 151866 Hom.: 39508 Cov.: 30 AF XY: 0.722 AC XY: 53619 AN XY: 74230

Gnomad4 AFR AF: 0.659

Gnomad4 AMR AF: 0.703

Gnomad4 ASJ AF: 0.698

Gnomad4 EAS AF: 0.725

Gnomad4 SAS AF: 0.669

Gnomad4 FIN AF: 0.857

Gnomad4 NFE AF: 0.740

Gnomad4 OTH AF: 0.694

Alfa AF: 0.732 Hom.: 13225

Bravo AF: 0.708

Asia WGS AF: 0.703 AC: 2442 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

Familial spontaneous pneumothorax Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Birt-Hogg-Dube syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
Cadd	Benign	0.30
Dann	Benign	0.72

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: rs7218795; hg19: chr17-17115566;