rs41364753

Variant names:

• chr17-17217001-C-G
• rs41364753
• NM_144997.7:c.1176+68G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_144997.7(FLCN):​c.1176+68G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0242 in 1,182,878 control chromosomes in the GnomAD database, including 507 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.035 (162 hom., cov: 33)
  • Exomes 𝑓: 0.023 (345 hom.)
• Consequence: FLCN NM_144997.7 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.871
• 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=-0.86).
• BP6: Variant 17-17217001-C-G is Benign according to our data. Variant chr17-17217001-C-G is described in ClinVar as Benign. ClinVar VariationId is 1284984.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.076 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FLCN	NM_144997.7	c.1176+68G>C		intron_variant	Intron 10 of 13	ENST00000285071.9	NP_659434.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FLCN	ENST00000285071.9	c.1176+68G>C		intron_variant	Intron 10 of 13	1	NM_144997.7	ENSP00000285071.4
ENSG00000264187	ENST00000427497.3	n.*10+68G>C		intron_variant	Intron 6 of 11	1		ENSP00000394249.3
FLCN	ENST00000577591.1	n.267G>C		non_coding_transcript_exon_variant	Exon 2 of 2	2
MPRIP	ENST00000578209.5	c.*18-489C>G		intron_variant	Intron 5 of 5	3		ENSP00000464276.1

Frequencies

GnomAD3 genomes AF: 0.0353 AC: 5379 AN: 152172 Hom.: 163 Cov.: 33

Gnomad AFR AF: 0.0783

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0199

Gnomad ASJ AF: 0.0305

Gnomad EAS AF: 0.00347

Gnomad SAS AF: 0.0186

Gnomad FIN AF: 0.00235

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0223

Gnomad OTH AF: 0.0301

GnomAD4 exome AF: 0.0226 AC: 23278 AN: 1030588 Hom.: 345 Cov.: 14 AF XY: 0.0222 AC XY: 11765 AN XY: 530880

African (AFR) AF: 0.0837 AC: 2098 AN: 25062

American (AMR) AF: 0.0126 AC: 536 AN: 42452

Ashkenazi Jewish (ASJ) AF: 0.0292 AC: 676 AN: 23186

East Asian (EAS) AF: 0.00832 AC: 312 AN: 37506

South Asian (SAS) AF: 0.0218 AC: 1661 AN: 76022

European-Finnish (FIN) AF: 0.00438 AC: 227 AN: 51774

Middle Eastern (MID) AF: 0.0357 AC: 152 AN: 4262

European-Non Finnish (NFE) AF: 0.0226 AC: 16385 AN: 724226

Other (OTH) AF: 0.0267 AC: 1231 AN: 46098

GnomAD4 genome AF: 0.0354 AC: 5386 AN: 152290 Hom.: 162 Cov.: 33 AF XY: 0.0344 AC XY: 2560 AN XY: 74478

African (AFR) AF: 0.0782 AC: 3249 AN: 41532

American (AMR) AF: 0.0199 AC: 304 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0305 AC: 106 AN: 3470

East Asian (EAS) AF: 0.00348 AC: 18 AN: 5172

South Asian (SAS) AF: 0.0188 AC: 91 AN: 4830

European-Finnish (FIN) AF: 0.00235 AC: 25 AN: 10624

Middle Eastern (MID) AF: 0.0476 AC: 14 AN: 294

European-Non Finnish (NFE) AF: 0.0223 AC: 1514 AN: 68036

Other (OTH) AF: 0.0298 AC: 63 AN: 2112

Alfa AF: 0.0294 Hom.: 11

Bravo AF: 0.0378

Asia WGS AF: 0.0240 AC: 82 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:2

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	1.2
DANN	Benign	0.56
PhyloP100		-0.87
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs41364753; hg19: chr17-17120315;