17-17213213-A-G

Variant names:

• chr17-17213213-A-G
• rs7224213
• NM_144997.7:c.*442T>C

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.*442T>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 0.0215 in 378,794 control chromosomes in the GnomAD database, including 123 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.024 (64 hom., cov: 32)
  • Exomes 𝑓: 0.020 (59 hom.)
• Consequence: FLCN NM_144997.7 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.755

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 17-17213213-A-G is Benign according to our data. Variant chr17-17213213-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 322051.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0242 (3686/152314) while in subpopulation AFR AF= 0.0402 (1672/41574). AF 95% confidence interval is 0.0386. There are 64 homozygotes in gnomad4. There are 1720 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 3686 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FLCN	NM_144997.7	c.*442T>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.*442T>C		3_prime_UTR_variant	Exon 14 of 14	1	NM_144997.7	ENSP00000285071.4
ENSG00000264187	ENST00000427497.3	n.*372+1772T>C		intron_variant	Intron 9 of 11	1		ENSP00000394249.3
MPRIP	ENST00000578209.5	c.*18-4277A>G		intron_variant	Intron 5 of 5	3		ENSP00000464276.1

Frequencies

GnomAD3 genomes AF: 0.0242 AC: 3685 AN: 152196 Hom.: 64 Cov.: 32

Gnomad AFR AF: 0.0403

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0187

Gnomad ASJ AF: 0.00749

Gnomad EAS AF: 0.00347

Gnomad SAS AF: 0.0186

Gnomad FIN AF: 0.00283

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0221

Gnomad OTH AF: 0.0224

GnomAD4 exome AF: 0.0196 AC: 4446 AN: 226480 Hom.: 59 Cov.: 0 AF XY: 0.0190 AC XY: 2177 AN XY: 114702

Gnomad4 AFR exome AF: 0.0426

Gnomad4 AMR exome AF: 0.0141

Gnomad4 ASJ exome AF: 0.00498

Gnomad4 EAS exome AF: 0.00773

Gnomad4 SAS exome AF: 0.0193

Gnomad4 FIN exome AF: 0.00612

Gnomad4 NFE exome AF: 0.0217

Gnomad4 OTH exome AF: 0.0201

GnomAD4 genome AF: 0.0242 AC: 3686 AN: 152314 Hom.: 64 Cov.: 32 AF XY: 0.0231 AC XY: 1720 AN XY: 74468

Gnomad4 AFR AF: 0.0402

Gnomad4 AMR AF: 0.0186

Gnomad4 ASJ AF: 0.00749

Gnomad4 EAS AF: 0.00347

Gnomad4 SAS AF: 0.0188

Gnomad4 FIN AF: 0.00283

Gnomad4 NFE AF: 0.0222

Gnomad4 OTH AF: 0.0222

Alfa AF: 0.0223 Hom.: 17

Bravo AF: 0.0255

Asia WGS AF: 0.0190 AC: 66 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial spontaneous pneumothorax Benign:1

Jan 12, 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. -

not provided Benign:1

May 12, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Birt-Hogg-Dube syndrome Benign:1

Jan 12, 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	-0.89
CADD	Benign	1.8
DANN	Benign	0.25
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs7224213; hg19: chr17-17116527;