17-17217085-G-T

Position:

• chr17-17217085-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 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 (★).

• 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

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

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.9

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FLCN	NM_144997.7	c.1160C>A	p.Ala387Asp	missense_variant	10/14	ENST00000285071.9	NP_659434.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FLCN	ENST00000285071.9	c.1160C>A	p.Ala387Asp	missense_variant	10/14	1	NM_144997.7	ENSP00000285071.4
ENSG00000264187	ENST00000427497.3	n.282C>A		non_coding_transcript_exon_variant	6/12	1		ENSP00000394249.3
MPRIP	ENST00000578209.5	c.*18-405G>T		intron_variant		3		ENSP00000464276.1
FLCN	ENST00000577591.1	n.183C>A		non_coding_transcript_exon_variant	2/2	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

Uncertain significance, criteria provided, single submitter

clinical testing

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

May 19, 2021

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 v4.3

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
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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-17120399;