Genetic Variant FIG4:p.Ser10Asn (chr6-109691464-G-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_014845.6(FIG4):c.29G>A(p.Ser10Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000000697 in 1,434,872 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

FIG4
NM_014845.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.81

Publications

0 publications found

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]

FIG4 links:

AK9 (HGNC:33814): (adenylate kinase 9) The protein encoded by this gene catalyzes the interconversion of nucleosides, possessing both nucleoside monophosphate and diphosphate kinase activities. The encoded protein uses these interconversions to maintain nucleoside homeostasis. [provided by RefSeq, Jul 2016]

AK9 Gene-Disease associations (from GenCC):

postsynaptic congenital myasthenic syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

AK9 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014845.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FIG4	NM_014845.6	MANE Select	c.29G>A	p.Ser10Asn	missense	Exon 1 of 23	NP_055660.1	Q92562

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FIG4	ENST00000230124.8	TSL:1 MANE Select	c.29G>A	p.Ser10Asn	missense	Exon 1 of 23	ENSP00000230124.4	Q92562
FIG4	ENST00000674884.1		c.29G>A	p.Ser10Asn	missense	Exon 1 of 23	ENSP00000502668.1	A0A6Q8PHH5
FIG4	ENST00000674744.1		c.29G>A	p.Ser10Asn	missense	Exon 1 of 23	ENSP00000501661.1	A0A6Q8PF62

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000491

AC:

AN:

203778

AF XY:

0.00000909

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000196

GnomAD4 exome

AF:

6.97e-7

AC:

AN:

1434872

Hom.:

Cov.:

AF XY:

0.00000141

AC XY:

AN XY:

711138

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32962

American (AMR)

AF:

0.00

AC:

AN:

41222

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25592

East Asian (EAS)

AF:

0.00

AC:

AN:

38334

South Asian (SAS)

AF:

0.00

AC:

AN:

82244

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51032

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5730

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1098474

Other (OTH)

AF:

0.0000169

AC:

AN:

59282

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000189

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Charcot-Marie-Tooth disease type 4 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.39

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.23

Eigen

Uncertain

0.33

Eigen_PC

Uncertain

0.38

FATHMM_MKL

Benign

0.19

LIST_S2

Benign

0.84

M_CAP

Benign

0.014

MetaRNN

Uncertain

0.49

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.2

PhyloP100

4.8

PrimateAI

Pathogenic

0.84

PROVEAN

Benign

-1.4

REVEL

Benign

0.054

Sift

Uncertain

0.0040

Sift4G

Benign

0.14

Polyphen

0.91

Vest4

0.57

MutPred

0.39

Gain of loop (P = 0.0097)

MVP

0.45

MPC

0.33

ClinPred

0.87

GERP RS

4.7

PromoterAI

0.032

Neutral

(source)

Varity_R

0.37

gMVP

0.33

Mutation Taster

=89/11

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over