rs775149348

Variant names:

• chr17-17213758-T-A
• rs775149348
• NM_144997.7:c.1637A>T

Your query was ambiguous. Multiple possible variants found:

• chr17-17213758-T-A
• chr17-17213758-T-C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_144997.7(FLCN):​c.1637A>T​(p.Asn546Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,892 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N546S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: FLCN NM_144997.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.74
• Publications: 0 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: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.904

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.1637A>T	p.Asn546Ile	missense	Exon 14 of 14	NP_659434.2
	FLCN	NM_001353229.2		c.1691A>T	p.Asn564Ile	missense	Exon 16 of 16	NP_001340158.1
	FLCN	NM_001353230.2		c.1637A>T	p.Asn546Ile	missense	Exon 15 of 15	NP_001340159.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLCN	ENST00000285071.9	TSL:1 MANE Select	c.1637A>T	p.Asn546Ile	missense	Exon 14 of 14	ENSP00000285071.4
	ENSG00000264187	ENST00000427497.3	TSL:1	n.*372+1227A>T		intron	N/A	ENSP00000394249.3
	FLCN	ENST00000962729.1		c.1742A>T	p.Asn581Ile	missense	Exon 16 of 16	ENSP00000632788.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251496 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461892 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727248

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112012

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Pathogenic	0.18
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.85	D
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	D
M_CAP	Pathogenic	0.36	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Uncertain	0.49	D
MutationAssessor	Benign	1.1	L
PhyloP100		7.7
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-2.9	D
REVEL	Pathogenic	0.71
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0080	D
Polyphen		1.0	D
Vest4		0.97
MutPred		0.62		Loss of loop (P = 0.0153)
MVP		0.72
MPC		1.2
ClinPred		0.97	D
GERP RS		3.5
Varity_R		0.86
gMVP		0.58

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: rs775149348; hg19: chr17-17117072;