NM_014845.6:c.290-2A>G

Variant names:

• chr6-109727107-A-G
• rs587777715
• NM_014845.6:c.290-2A>G

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_014845.6(FIG4):​c.290-2A>G variant causes a splice acceptor, intron 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. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: FIG4 NM_014845.6 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: 8.97
• Publications: 1 publications found

Genes affected

FIG4 (HGNC:16873): (FIG4 phosphoinositide 5-phosphatase) The protein encoded by this gene belongs to the SAC domain-containing protein gene family. The SAC domain, approximately 400 amino acids in length and consisting of seven conserved motifs, has been shown to possess phosphoinositide phosphatase activity. The yeast homolog, Sac1p, is involved in the regulation of various phosphoinositides, and affects diverse cellular functions such as actin cytoskeleton organization, Golgi function, and maintenance of vacuole morphology. Membrane-bound phosphoinositides function as signaling molecules and play a key role in vesicle trafficking in eukaryotic cells. Mutations in this gene have been associated with Charcot-Marie-Tooth disease, type 4J. [provided by RefSeq, Jul 2008]

FIG4 Gene-Disease associations (from GenCC):

• Charcot-Marie-Tooth disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen, Illumina
• Charcot-Marie-Tooth disease type 4J

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics, Laboratory for Molecular Medicine
• Yunis-Varon syndrome

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, G2P
• amyotrophic lateral sclerosis type 11

  Inheritance: Unknown, AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Genomics England PanelApp
• amyotrophic lateral sclerosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• bilateral parasagittal parieto-occipital polymicrogyria

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 5.3, offset of 10, new splice context is: tgttgcatgggttttgtcAGgtt. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 6-109727107-A-G is Pathogenic according to our data. Variant chr6-109727107-A-G is described in CliVar as Pathogenic. Clinvar id is 638361.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-109727107-A-G is described in CliVar as Pathogenic. Clinvar id is 638361.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-109727107-A-G is described in CliVar as Pathogenic. Clinvar id is 638361.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-109727107-A-G is described in CliVar as Pathogenic. Clinvar id is 638361.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-109727107-A-G is described in CliVar as Pathogenic. Clinvar id is 638361.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-109727107-A-G is described in CliVar as Pathogenic. Clinvar id is 638361.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-109727107-A-G is described in CliVar as Pathogenic. Clinvar id is 638361.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-109727107-A-G is described in CliVar as Pathogenic. Clinvar id is 638361.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-109727107-A-G is described in CliVar as Pathogenic. Clinvar id is 638361.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-109727107-A-G is described in CliVar as Pathogenic. Clinvar id is 638361.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-109727107-A-G is described in CliVar as Pathogenic. Clinvar id is 638361.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-109727107-A-G is described in CliVar as Pathogenic. Clinvar id is 638361.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-109727107-A-G is described in CliVar as Pathogenic. Clinvar id is 638361.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-109727107-A-G is described in CliVar as Pathogenic. Clinvar id is 638361.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-109727107-A-G is described in CliVar as Pathogenic. Clinvar id is 638361.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-109727107-A-G is described in CliVar as Pathogenic. Clinvar id is 638361.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-109727107-A-G is described in CliVar as Pathogenic. Clinvar id is 638361.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-109727107-A-G is described in CliVar as Pathogenic. Clinvar id is 638361.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-109727107-A-G is described in CliVar as Pathogenic. Clinvar id is 638361.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-109727107-A-G is described in CliVar as Pathogenic. Clinvar id is 638361.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-109727107-A-G is described in CliVar as Pathogenic. Clinvar id is 638361.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-109727107-A-G is described in CliVar as Pathogenic. Clinvar id is 638361.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-109727107-A-G is described in CliVar as Pathogenic. Clinvar id is 638361.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-109727107-A-G is described in CliVar as Pathogenic. Clinvar id is 638361.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FIG4	NM_014845.6	c.290-2A>G		splice_acceptor_variant, intron_variant	Intron 3 of 22	ENST00000230124.8	NP_055660.1
FIG4	XM_011536281.4	c.227-2A>G		splice_acceptor_variant, intron_variant	Intron 3 of 22		XP_011534583.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FIG4	ENST00000230124.8	c.290-2A>G		splice_acceptor_variant, intron_variant	Intron 3 of 22	1	NM_014845.6	ENSP00000230124.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

Submissions by phenotype

Bilateral parasagittal parieto-occipital polymicrogyria Pathogenic:1

Apr 27, 2019

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Yunis-Varon syndrome Pathogenic:1

Apr 27, 2019

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Charcot-Marie-Tooth disease type 4J Pathogenic:1

Apr 27, 2019

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.23
CADD	Pathogenic	30
DANN	Uncertain	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.94
FATHMM_MKL	Pathogenic	0.99	D
PhyloP100		9.0
GERP RS		5.0
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.72		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.72		Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs587777715; hg19: chr6-110048310;