NM_144997.7:c.*442T>C

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 4 publications found

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

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 3686 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_144997.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLCN	NM_144997.7	MANE Select	c.*442T>C		3_prime_UTR	Exon 14 of 14	NP_659434.2
	FLCN	NM_001353229.2		c.*442T>C		3_prime_UTR	Exon 16 of 16	NP_001340158.1
	FLCN	NM_001353230.2		c.*442T>C		3_prime_UTR	Exon 15 of 15	NP_001340159.1	Q8NFG4-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLCN	ENST00000285071.9	TSL:1 MANE Select	c.*442T>C		3_prime_UTR	Exon 14 of 14	ENSP00000285071.4	Q8NFG4-1
	ENSG00000264187	ENST00000427497.3	TSL:1	n.*372+1772T>C		intron	N/A	ENSP00000394249.3	J3QW42
	FLCN	ENST00000962729.1		c.*442T>C		3_prime_UTR	Exon 16 of 16	ENSP00000632788.1

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

African (AFR) AF: 0.0426 AC: 362 AN: 8496

American (AMR) AF: 0.0141 AC: 124 AN: 8780

Ashkenazi Jewish (ASJ) AF: 0.00498 AC: 43 AN: 8640

East Asian (EAS) AF: 0.00773 AC: 139 AN: 17976

South Asian (SAS) AF: 0.0193 AC: 509 AN: 26440

European-Finnish (FIN) AF: 0.00612 AC: 43 AN: 7030

Middle Eastern (MID) AF: 0.0300 AC: 31 AN: 1034

European-Non Finnish (NFE) AF: 0.0217 AC: 2910 AN: 133924

Other (OTH) AF: 0.0201 AC: 285 AN: 14160

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

African (AFR) AF: 0.0402 AC: 1672 AN: 41574

American (AMR) AF: 0.0186 AC: 285 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00749 AC: 26 AN: 3470

East Asian (EAS) AF: 0.00347 AC: 18 AN: 5182

South Asian (SAS) AF: 0.0188 AC: 91 AN: 4828

European-Finnish (FIN) AF: 0.00283 AC: 30 AN: 10618

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.0222 AC: 1507 AN: 68030

Other (OTH) AF: 0.0222 AC: 47 AN: 2116

Alfa AF: 0.0235 Hom.: 30

Bravo AF: 0.0255

Asia WGS AF: 0.0190 AC: 66 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Birt-Hogg-Dube syndrome (1)
-	-	1	Familial spontaneous pneumothorax (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.8
DANN	Benign	0.25
PhyloP100		0.76
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs7224213; hg19: chr17-17116527;