rs9481005

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_StrongBP6_Moderate

The NM_014845.6(FIG4):c.2377-10T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000314 in 1,496,866 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000031 ( 0 hom. )

Consequence

FIG4
NM_014845.6 intron

Scores

Splicing: ADA: 0.01547

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.129

Publications

1 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 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

FIG4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.71).

BP6

Variant 6-109792572-T-A is Benign according to our data. Variant chr6-109792572-T-A is described in CliVar as Likely_benign. Clinvar id is 476858.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-109792572-T-A is described in CliVar as Likely_benign. Clinvar id is 476858.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-109792572-T-A is described in CliVar as Likely_benign. Clinvar id is 476858.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-109792572-T-A is described in CliVar as Likely_benign. Clinvar id is 476858.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-109792572-T-A is described in CliVar as Likely_benign. Clinvar id is 476858.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-109792572-T-A is described in CliVar as Likely_benign. Clinvar id is 476858.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-109792572-T-A is described in CliVar as Likely_benign. Clinvar id is 476858.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-109792572-T-A is described in CliVar as Likely_benign. Clinvar id is 476858.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-109792572-T-A is described in CliVar as Likely_benign. Clinvar id is 476858.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-109792572-T-A is described in CliVar as Likely_benign. Clinvar id is 476858.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-109792572-T-A is described in CliVar as Likely_benign. Clinvar id is 476858.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-109792572-T-A is described in CliVar as Likely_benign. Clinvar id is 476858.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-109792572-T-A is described in CliVar as Likely_benign. Clinvar id is 476858.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-109792572-T-A is described in CliVar as Likely_benign. Clinvar id is 476858.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-109792572-T-A is described in CliVar as Likely_benign. Clinvar id is 476858.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-109792572-T-A is described in CliVar as Likely_benign. Clinvar id is 476858.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 link	c.2377-10T>A		intron_variant	Intron 20 of 22	ENST00000230124.8	NP_055660.1	Q92562
FIG4	XM_011536281.4 link	c.2314-10T>A		intron_variant	Intron 20 of 22		XP_011534583.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FIG4	ENST00000230124.8 link	c.2377-10T>A		intron_variant	Intron 20 of 22	1	NM_014845.6	ENSP00000230124.4		Q92562

Frequencies

GnomAD3 genomes

AF:

0.0000332

AC:

AN:

150780

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000243

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000591

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000165

AC:

AN:

242506

AF XY:

0.0000229

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:

0.0000360

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000312

AC:

AN:

1345976

Hom.:

Cov.:

AF XY:

0.0000326

AC XY:

AN XY:

675006

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

30892

American (AMR)

AF:

0.00

AC:

AN:

42796

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25252

East Asian (EAS)

AF:

0.00

AC:

AN:

38890

South Asian (SAS)

AF:

0.0000122

AC:

AN:

81746

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52088

Middle Eastern (MID)

AF:

0.000180

AC:

AN:

5554

European-Non Finnish (NFE)

AF:

0.0000375

AC:

AN:

1012384

Other (OTH)

AF:

0.0000355

AC:

AN:

56374

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.352

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

AF:

0.0000331

AC:

AN:

150890

Hom.:

Cov.:

AF XY:

0.0000407

AC XY:

AN XY:

73674

show subpopulations

African (AFR)

AF:

0.0000242

AC:

AN:

41344

American (AMR)

AF:

0.00

AC:

AN:

15048

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3456

East Asian (EAS)

AF:

0.00

AC:

AN:

5072

South Asian (SAS)

AF:

0.00

AC:

AN:

4710

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10290

Middle Eastern (MID)

AF:

0.00

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.0000591

AC:

AN:

67690

Other (OTH)

AF:

0.00

AC:

AN:

2080

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.515

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000113

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Charcot-Marie-Tooth disease type 4

Benign:1

Aug 13, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.71

CADD

Benign

1.5

(source)

DANN

Benign

0.76

PhyloP100

-0.13

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.015

dbscSNV1_RF

Benign

0.30

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over