17-17217085-G-T

Variant names:

• chr17-17217085-G-T
• rs1431737113
• NM_144997.7:c.1160C>A

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.1160C>A​(p.Ala387Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A387V) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: FLCN NM_144997.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.17
• 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, 0.9

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.1160C>A	p.Ala387Asp	missense	Exon 10 of 14	NP_659434.2
	FLCN	NM_001353229.2		c.1214C>A	p.Ala405Asp	missense	Exon 12 of 16	NP_001340158.1
	FLCN	NM_001353230.2		c.1160C>A	p.Ala387Asp	missense	Exon 11 of 15	NP_001340159.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLCN	ENST00000285071.9	TSL:1 MANE Select	c.1160C>A	p.Ala387Asp	missense	Exon 10 of 14	ENSP00000285071.4
	ENSG00000264187	ENST00000427497.3	TSL:1	n.282C>A		non_coding_transcript_exon	Exon 6 of 12	ENSP00000394249.3
	FLCN	ENST00000577591.1	TSL:2	n.183C>A		non_coding_transcript_exon	Exon 2 of 2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Birt-Hogg-Dube syndrome Uncertain:1

May 19, 2021

Diagnostics Services (NGS), CSIR - Centre For Cellular And Molecular Biology

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1160C>A variant is not present in publicly available population databases like 1000 Genomes, Exome Variant Server (EVS), Exome Aggregation Consortium (ExAC), Genome Aggregation Database (gnomAD) and dbSNP. The variant is also not present in Indian Exome Database [Kausthubham et al. Hum Mutat, 2021] and in our in-house exome database. The variant was not earlier reported to ClinVar, Human Genome Mutation Database (HGMD) and/or OMIM databases in any affected individuals. A different missense variation in the same position (NM_144997.7:c.1160C>T:p.Ala387Val) was earlier reported to ClinVar multiple times as uncertain significance (Accession: VCV000460584.4) in association with multiple fibrofoliculomas and hereditary cancer-predisposing syndrome. The amino acid position is highly conserved and in-silico pathogenicity prediction programs like SIFT, PolyPhen-3, MutationTaster2, CADD etc. predicted this variant to be likely disease causing but these predictions have not been confirmed by any published functional studies. Due to lack of enough evidence the variant has been classified as uncertain significance.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.86	D
Eigen	Pathogenic	0.69
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.86	D
M_CAP	Pathogenic	0.32	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Pathogenic	0.85	D
MutationAssessor	Benign	1.8	L
PhyloP100		9.2
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-2.8	D
REVEL	Pathogenic	0.83
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.016	D
Polyphen		1.0	D
Vest4		0.95
MutPred		0.55		Loss of helix (P = 0.0444)
MVP		0.93
MPC		1.4
ClinPred		0.98	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.82
gMVP		0.92

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: rs1431737113; hg19: chr17-17120399;