chr17-17212744-C-T

Position:

• chr17-17212744-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_144997.7(FLCN):​c.*911G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00333 in 193,038 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0035 (3 hom., cov: 31)
  • Exomes 𝑓: 0.0027 (1 hom.)
• Consequence: FLCN NM_144997.7 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 0.212

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 17-17212744-C-T is Benign according to our data. Variant chr17-17212744-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 322042.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0035 (533/152140) while in subpopulation NFE AF= 0.00435 (296/67998). AF 95% confidence interval is 0.00395. There are 3 homozygotes in gnomad4. There are 307 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 533 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FLCN	NM_144997.7	c.*911G>A		3_prime_UTR_variant	14/14	ENST00000285071.9	NP_659434.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FLCN	ENST00000285071	c.*911G>A		3_prime_UTR_variant	14/14	1	NM_144997.7	ENSP00000285071.4
ENSG00000264187	ENST00000427497.3	n.*372+2241G>A		intron_variant		1		ENSP00000394249.3
MPRIP	ENST00000578209.5	c.*18-4746C>T		intron_variant		3		ENSP00000464276.1

Frequencies

GnomAD3 genomes AF: 0.00351 AC: 533 AN: 152022 Hom.: 3 Cov.: 31

Gnomad AFR AF: 0.000580

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00144

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00373

Gnomad FIN AF: 0.0153

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00435

Gnomad OTH AF: 0.00479

GnomAD4 exome AF: 0.00269 AC: 110 AN: 40898 Hom.: 1 Cov.: 0 AF XY: 0.00256 AC XY: 49 AN XY: 19110

Gnomad4 AFR exome AF: 0.000632

Gnomad4 AMR exome AF: 0.00477

Gnomad4 ASJ exome AF: 0.000382

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00289

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00393

Gnomad4 OTH exome AF: 0.00148

GnomAD4 genome AF: 0.00350 AC: 533 AN: 152140 Hom.: 3 Cov.: 31 AF XY: 0.00413 AC XY: 307 AN XY: 74370

Gnomad4 AFR AF: 0.000578

Gnomad4 AMR AF: 0.00144

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00374

Gnomad4 FIN AF: 0.0153

Gnomad4 NFE AF: 0.00435

Gnomad4 OTH AF: 0.00474

Alfa AF: 0.00365 Hom.: 0

Bravo AF: 0.00228

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

Familial spontaneous pneumothorax Benign:1

Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely 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	-0.92
CADD	Benign	1.6
DANN	Benign	0.18

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: rs571893996; hg19: chr17-17116058;