rs2295837

Variant names:

• chr6-109743725-A-C
• rs2295837
• NM_014845.6:c.1090A>C

Your query was ambiguous. Multiple possible variants found:

• chr6-109743725-A-C
• chr6-109743725-A-T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_014845.6(FIG4):​c.1090A>C​(p.Met364Leu) 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 benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M364K) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FIG4 NM_014845.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 8.93
• Publications: 28 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.28544408).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FIG4	NM_014845.6	c.1090A>C	p.Met364Leu	missense_variant	Exon 10 of 23	ENST00000230124.8	NP_055660.1
FIG4	XM_011536281.4	c.1027A>C	p.Met343Leu	missense_variant	Exon 10 of 23		XP_011534583.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FIG4	ENST00000230124.8	c.1090A>C	p.Met364Leu	missense_variant	Exon 10 of 23	1	NM_014845.6	ENSP00000230124.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Dec 15, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nicholson, 2011 Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Charcot-Marie-Tooth disease type 4 Uncertain:1

Jun 04, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This missense change has been observed in the heterozygous state in individual(s) tested for clinical suspicion of Charcot-Marie-Tooth disease (PMID: 21705420). This missense change has also been observed in individual(s) with amyotrophic lateral sclerosis (PMID: 23336365). This variant is not present in population databases (ExAC no frequency). This sequence change replaces methionine with leucine at codon 364 of the FIG4 protein (p.Met364Leu). The methionine residue is moderately conserved and there is a small physicochemical difference between methionine and leucine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	19
DANN	Benign	0.93
DEOGEN2	Benign	0.23	T
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.11
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.0088	T
MetaRNN	Benign	0.29	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.7	N
PhyloP100		8.9
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	1.1	N
REVEL	Benign	0.18
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.029	B
Vest4		0.26
MutPred		0.24		Loss of MoRF binding (P = 0.3574);
MVP		0.19
MPC		0.29
ClinPred		0.84	D
GERP RS		4.9
Varity_R		0.20
gMVP		0.64
Mutation Taster		=89/11	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2295837; hg19: chr6-110064928;