rs551339249

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_014845.6(FIG4):​c.350C>A​(p.Ala117Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,458,082 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.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

FIG4
NM_014845.6 missense

Scores

14
3
2

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.62
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.963

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
FIG4NM_014845.6 linkc.350C>A p.Ala117Glu missense_variant Exon 4 of 23 ENST00000230124.8 NP_055660.1 Q92562
FIG4XM_011536281.4 linkc.287C>A p.Ala96Glu missense_variant Exon 4 of 23 XP_011534583.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
FIG4ENST00000230124.8 linkc.350C>A p.Ala117Glu missense_variant Exon 4 of 23 1 NM_014845.6 ENSP00000230124.4 Q92562

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000206
AC:
3
AN:
1458082
Hom.:
0
Cov.:
29
AF XY:
0.00
AC XY:
0
AN XY:
725628
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000271
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.36
D
BayesDel_noAF
Pathogenic
0.28
CADD
Pathogenic
26
DANN
Uncertain
0.99
DEOGEN2
Pathogenic
0.85
D;.;.
Eigen
Pathogenic
0.94
Eigen_PC
Pathogenic
0.85
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.96
D;D;D
M_CAP
Benign
0.078
D
MetaRNN
Pathogenic
0.96
D;D;D
MetaSVM
Uncertain
0.16
D
MutationAssessor
Pathogenic
3.3
M;.;.
PrimateAI
Pathogenic
0.90
D
PROVEAN
Pathogenic
-4.8
D;D;D
REVEL
Pathogenic
0.69
Sift
Pathogenic
0.0
D;D;D
Sift4G
Pathogenic
0.0
D;D;D
Polyphen
1.0
D;.;.
Vest4
0.96
MutPred
0.87
Gain of disorder (P = 0.021);.;.;
MVP
0.78
MPC
1.1
ClinPred
1.0
D
GERP RS
5.0
Varity_R
0.98
gMVP
0.89

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: chr6-110048372; API