NM_014845.6:c.647-18C>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_014845.6(FIG4):c.647-18C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.374 in 1,579,074 control chromosomes in the GnomAD database, including 113,384 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

Frequency

Genomes: 𝑓 0.34 ( 9275 hom., cov: 32)

Exomes 𝑓: 0.38 ( 104109 hom. )

Consequence

FIG4
NM_014845.6 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -0.200

Publications

9 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: Illumina, ClinGen
Charcot-Marie-Tooth disease type 4J
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Laboratory for Molecular Medicine, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)
amyotrophic lateral sclerosis type 11
Inheritance: AD, Unknown Classification: STRONG, LIMITED Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
Yunis-Varon syndrome
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet
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: Benign. The variant received -20 ACMG points.

BP4

This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 1 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.74).

BP6

Variant 6-109738307-C-A is Benign according to our data. Variant chr6-109738307-C-A is described in ClinVar as Benign. ClinVar VariationId is 260451.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.438 is higher than 0.05.

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.647-18C>A		intron	N/A	NP_055660.1	Q92562

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
FIG4	ENST00000230124.8	TSL:1 MANE Select	c.647-18C>A	intron	N/A	ENSP00000230124.4	Q92562
FIG4	ENST00000674884.1		c.665-18C>A	intron	N/A	ENSP00000502668.1	A0A6Q8PHH5
FIG4	ENST00000674744.1		c.641-18C>A	intron	N/A	ENSP00000501661.1	A0A6Q8PF62

Frequencies

GnomAD3 genomes

AF:

0.338

AC:

51244

AN:

151660

Hom.:

9271

Cov.:

show subpopulations

Gnomad AFR

AF:

0.188

Gnomad AMI

AF:

0.295

Gnomad AMR

AF:

0.407

Gnomad ASJ

AF:

0.482

Gnomad EAS

AF:

0.402

Gnomad SAS

AF:

0.453

Gnomad FIN

AF:

0.410

Gnomad MID

AF:

0.449

Gnomad NFE

AF:

0.381

Gnomad OTH

AF:

0.362

GnomAD2 exomes

AF:

0.391

AC:

97958

AN:

250508

AF XY:

0.397

show subpopulations

Gnomad AFR exome

AF:

0.179

Gnomad AMR exome

AF:

0.428

Gnomad ASJ exome

AF:

0.472

Gnomad EAS exome

AF:

0.375

Gnomad FIN exome

AF:

0.417

Gnomad NFE exome

AF:

0.384

Gnomad OTH exome

AF:

0.406

GnomAD4 exome

AF:

0.378

AC:

539988

AN:

1427296

Hom.:

104109

Cov.:

AF XY:

0.382

AC XY:

271824

AN XY:

711978

show subpopulations

African (AFR)

AF:

0.179

AC:

5889

AN:

32968

American (AMR)

AF:

0.427

AC:

19001

AN:

44546

Ashkenazi Jewish (ASJ)

AF:

0.471

AC:

12170

AN:

25832

East Asian (EAS)

AF:

0.420

AC:

16566

AN:

39454

South Asian (SAS)

AF:

0.444

AC:

37917

AN:

85446

European-Finnish (FIN)

AF:

0.416

AC:

22181

AN:

53280

Middle Eastern (MID)

AF:

0.414

AC:

2350

AN:

5678

European-Non Finnish (NFE)

AF:

0.371

AC:

401326

AN:

1080924

Other (OTH)

AF:

0.382

AC:

22588

AN:

59168

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.448

Heterozygous variant carriers

14732

29464

44197

58929

73661

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

12454

24908

37362

49816

62270

<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:

0.338

AC:

51273

AN:

151778

Hom.:

9275

Cov.:

AF XY:

0.342

AC XY:

25335

AN XY:

74174

show subpopulations

African (AFR)

AF:

0.188

AC:

7791

AN:

41398

American (AMR)

AF:

0.407

AC:

6202

AN:

15234

Ashkenazi Jewish (ASJ)

AF:

0.482

AC:

1674

AN:

3470

East Asian (EAS)

AF:

0.402

AC:

2070

AN:

5146

South Asian (SAS)

AF:

0.454

AC:

2185

AN:

4816

European-Finnish (FIN)

AF:

0.410

AC:

4308

AN:

10510

Middle Eastern (MID)

AF:

0.446

AC:

131

AN:

294

European-Non Finnish (NFE)

AF:

0.381

AC:

25882

AN:

67904

Other (OTH)

AF:

0.363

AC:

763

AN:

2100

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1700

3400

5099

6799

8499

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

518

1036

1554

2072

2590

<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:

0.361

Hom.:

2342

Bravo

AF:

0.332

Asia WGS

AF:

0.422

AC:

1465

AN:

3476

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (6)

Charcot-Marie-Tooth disease (1)

Charcot-Marie-Tooth disease type 4 (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.74

CADD

Benign

(source)

DANN

Benign

0.79

PhyloP100

-0.20

BranchPoint Hunter

1.0

Mutation Taster

=100/0

polymorphism (auto)

(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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over