17-17213098-A-G

Variant names:

• chr17-17213098-A-G
• rs3803761
• NM_144997.7:c.*557T>C

Variant summary

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

The NM_144997.7(FLCN):​c.*557T>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 0.715 in 258,560 control chromosomes in the GnomAD database, including 66,584 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.71 (39164 hom., cov: 30)
  • Exomes 𝑓: 0.72 (27420 hom.)
• Consequence: FLCN NM_144997.7 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.144

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=-0.88).
• BP6: Variant 17-17213098-A-G is Benign according to our data. Variant chr17-17213098-A-G is described in ClinVar as [Benign]. Clinvar id is 322048.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.73 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FLCN	NM_144997.7	c.*557T>C		3_prime_UTR_variant	Exon 14 of 14	ENST00000285071.9	NP_659434.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FLCN	ENST00000285071	c.*557T>C		3_prime_UTR_variant	Exon 14 of 14	1	NM_144997.7	ENSP00000285071.4
ENSG00000264187	ENST00000427497.3	n.*372+1887T>C		intron_variant	Intron 9 of 11	1		ENSP00000394249.3
MPRIP	ENST00000578209.5	c.*18-4392A>G		intron_variant	Intron 5 of 5	3		ENSP00000464276.1

Frequencies

GnomAD3 genomes AF: 0.715 AC: 108627 AN: 151904 Hom.: 39156 Cov.: 30

Gnomad AFR AF: 0.657

Gnomad AMI AF: 0.850

Gnomad AMR AF: 0.700

Gnomad ASJ AF: 0.696

Gnomad EAS AF: 0.725

Gnomad SAS AF: 0.662

Gnomad FIN AF: 0.854

Gnomad MID AF: 0.602

Gnomad NFE AF: 0.735

Gnomad OTH AF: 0.698

GnomAD4 exome AF: 0.716 AC: 76274 AN: 106538 Hom.: 27420 Cov.: 0 AF XY: 0.713 AC XY: 36118 AN XY: 50646

Gnomad4 AFR exome AF: 0.651

Gnomad4 AMR exome AF: 0.709

Gnomad4 ASJ exome AF: 0.682

Gnomad4 EAS exome AF: 0.698

Gnomad4 SAS exome AF: 0.677

Gnomad4 FIN exome AF: 0.815

Gnomad4 NFE exome AF: 0.729

Gnomad4 OTH exome AF: 0.722

GnomAD4 genome AF: 0.715 AC: 108678 AN: 152022 Hom.: 39164 Cov.: 30 AF XY: 0.719 AC XY: 53424 AN XY: 74310

Gnomad4 AFR AF: 0.657

Gnomad4 AMR AF: 0.699

Gnomad4 ASJ AF: 0.696

Gnomad4 EAS AF: 0.725

Gnomad4 SAS AF: 0.664

Gnomad4 FIN AF: 0.854

Gnomad4 NFE AF: 0.735

Gnomad4 OTH AF: 0.690

Alfa AF: 0.727 Hom.: 83243

Bravo AF: 0.704

Asia WGS AF: 0.702 AC: 2438 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

May 12, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 28222720) -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Familial spontaneous pneumothorax Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	-0.88
CADD	Benign	1.8
DANN	Benign	0.52
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
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

Publications

LitVar

Other links and lift over

dbSNP: rs3803761; hg19: chr17-17116412;