rs41442248

Variant names:

• chr17-17214864-G-A
• rs41442248
• NM_144997.7:c.1538+121C>T

Your query was ambiguous. Multiple possible variants found:

• chr17-17214864-G-A
• chr17-17214864-G-T

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.1538+121C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0249 in 1,072,898 control chromosomes in the GnomAD database, including 461 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.023 (76 hom., cov: 32)
  • Exomes 𝑓: 0.025 (385 hom.)
• Consequence: FLCN NM_144997.7 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.87
• Publications: 2 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=-0.95).
• BP6: Variant 17-17214864-G-A is Benign according to our data. Variant chr17-17214864-G-A is described in ClinVar as Benign. ClinVar VariationId is 1292853.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0231 (3521/152124) while in subpopulation NFE AF = 0.0274 (1863/67994). AF 95% confidence interval is 0.0264. There are 76 homozygotes in GnomAd4. There are 1809 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 3521 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FLCN	NM_144997.7	c.1538+121C>T		intron_variant	Intron 13 of 13	ENST00000285071.9	NP_659434.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FLCN	ENST00000285071.9	c.1538+121C>T		intron_variant	Intron 13 of 13	1	NM_144997.7	ENSP00000285071.4
ENSG00000264187	ENST00000427497.3	n.*372+121C>T		intron_variant	Intron 9 of 11	1		ENSP00000394249.3
MPRIP	ENST00000578209.5	c.*18-2626G>A		intron_variant	Intron 5 of 5	3		ENSP00000464276.1

Frequencies

GnomAD3 genomes AF: 0.0232 AC: 3525 AN: 152006 Hom.: 76 Cov.: 32

Gnomad AFR AF: 0.00527

Gnomad AMI AF: 0.0395

Gnomad AMR AF: 0.0257

Gnomad ASJ AF: 0.0326

Gnomad EAS AF: 0.000387

Gnomad SAS AF: 0.0151

Gnomad FIN AF: 0.0723

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0274

Gnomad OTH AF: 0.0220

GnomAD4 exome AF: 0.0252 AC: 23247 AN: 920774 Hom.: 385 AF XY: 0.0252 AC XY: 12015 AN XY: 476590

African (AFR) AF: 0.00533 AC: 122 AN: 22886

American (AMR) AF: 0.0164 AC: 624 AN: 38036

Ashkenazi Jewish (ASJ) AF: 0.0351 AC: 780 AN: 22238

East Asian (EAS) AF: 0.00 AC: 0 AN: 35376

South Asian (SAS) AF: 0.0174 AC: 1260 AN: 72592

European-Finnish (FIN) AF: 0.0628 AC: 2586 AN: 41182

Middle Eastern (MID) AF: 0.0361 AC: 112 AN: 3104

European-Non Finnish (NFE) AF: 0.0258 AC: 16581 AN: 642954

Other (OTH) AF: 0.0279 AC: 1182 AN: 42406

GnomAD4 genome AF: 0.0231 AC: 3521 AN: 152124 Hom.: 76 Cov.: 32 AF XY: 0.0243 AC XY: 1809 AN XY: 74388

African (AFR) AF: 0.00528 AC: 219 AN: 41510

American (AMR) AF: 0.0257 AC: 392 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.0326 AC: 113 AN: 3470

East Asian (EAS) AF: 0.000388 AC: 2 AN: 5156

South Asian (SAS) AF: 0.0153 AC: 74 AN: 4824

European-Finnish (FIN) AF: 0.0723 AC: 765 AN: 10586

Middle Eastern (MID) AF: 0.0374 AC: 11 AN: 294

European-Non Finnish (NFE) AF: 0.0274 AC: 1863 AN: 67994

Other (OTH) AF: 0.0218 AC: 46 AN: 2114

Alfa AF: 0.0279 Hom.: 8

Bravo AF: 0.0195

Asia WGS AF: 0.00693 AC: 24 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 26, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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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	-0.95
CADD	Benign	0.012
DANN	Benign	0.67
PhyloP100		-1.9
Mutation Taster		=100/0	polymorphism

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: rs41442248; hg19: chr17-17118178;