NM_144997.7:c.-228+994A>G

Variant names:

• chr17-17235918-T-C
• rs41337846
• NM_144997.7:c.-228+994A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_144997.7(FLCN):​c.-228+994A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.148 in 152,108 control chromosomes in the GnomAD database, including 1,949 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.15 (1947 hom., cov: 32)
  • Exomes 𝑓: 0.17 (2 hom.)
• Consequence: FLCN NM_144997.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.92
• 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]

FLCN Gene-Disease associations (from GenCC):

• Birt-Hogg-Dube syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet, ClinGen
• Birt-Hogg-Dube syndrome 1

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P, Ambry Genetics
• familial spontaneous pneumothorax

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, Ambry Genetics
• renal carcinoma

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• colorectal cancer

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ENSG00000264187 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.234 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLCN	NM_144997.7	MANE Select	c.-228+994A>G		intron	N/A	NP_659434.2
	FLCN	NM_001353229.2		c.-228+558A>G		intron	N/A	NP_001340158.1
	FLCN	NM_001353230.2		c.-511+994A>G		intron	N/A	NP_001340159.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLCN	ENST00000285071.9	TSL:1 MANE Select	c.-228+994A>G		intron	N/A	ENSP00000285071.4
	FLCN	ENST00000389169.9	TSL:1	c.-228+994A>G		intron	N/A	ENSP00000373821.5
	ENSG00000264187	ENST00000427497.3	TSL:1	n.-228+994A>G		intron	N/A	ENSP00000394249.3

Frequencies

GnomAD3 genomes AF: 0.148 AC: 22500 AN: 151960 Hom.: 1944 Cov.: 32

Gnomad AFR AF: 0.0561

Gnomad AMI AF: 0.160

Gnomad AMR AF: 0.153

Gnomad ASJ AF: 0.209

Gnomad EAS AF: 0.219

Gnomad SAS AF: 0.244

Gnomad FIN AF: 0.141

Gnomad MID AF: 0.177

Gnomad NFE AF: 0.188

Gnomad OTH AF: 0.172

GnomAD4 exome AF: 0.167 AC: 5 AN: 30 Hom.: 2 Cov.: 0 AF XY: 0.250 AC XY: 5 AN XY: 20

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.192 AC: 5 AN: 26

Other (OTH) AF: 0.00 AC: 0 AN: 4

GnomAD4 genome AF: 0.148 AC: 22516 AN: 152078 Hom.: 1947 Cov.: 32 AF XY: 0.149 AC XY: 11083 AN XY: 74336

African (AFR) AF: 0.0562 AC: 2332 AN: 41516

American (AMR) AF: 0.152 AC: 2327 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.209 AC: 723 AN: 3458

East Asian (EAS) AF: 0.219 AC: 1127 AN: 5156

South Asian (SAS) AF: 0.246 AC: 1185 AN: 4820

European-Finnish (FIN) AF: 0.141 AC: 1493 AN: 10574

Middle Eastern (MID) AF: 0.177 AC: 52 AN: 294

European-Non Finnish (NFE) AF: 0.188 AC: 12764 AN: 67966

Other (OTH) AF: 0.174 AC: 367 AN: 2108

Alfa AF: 0.152 Hom.: 285

Bravo AF: 0.146

Asia WGS AF: 0.189 AC: 660 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.11
DANN	Benign	0.48
PhyloP100		-2.9
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: rs41337846; hg19: chr17-17139232;