chr6-109727274-G-A

Variant names:

• chr6-109727274-G-A
• rs190287033
• NM_014845.6:c.446+9G>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_014845.6(FIG4):​c.446+9G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00117 in 1,572,892 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (1 hom.)
• Consequence: FIG4 NM_014845.6 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:11
• Conservation: PhyloP100: 0.0380
• Publications: 0 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: 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

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 6-109727274-G-A is Benign according to our data. Variant chr6-109727274-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 381005.

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.446+9G>A		intron	N/A	NP_055660.1	Q92562

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FIG4	ENST00000230124.8	TSL:1 MANE Select	c.446+9G>A		intron	N/A	ENSP00000230124.4	Q92562
	FIG4	ENST00000674884.1		c.446+9G>A		intron	N/A	ENSP00000502668.1	A0A6Q8PHH5
	FIG4	ENST00000674744.1		c.446+9G>A		intron	N/A	ENSP00000501661.1	A0A6Q8PF62

Frequencies

GnomAD3 genomes AF: 0.00120 AC: 138 AN: 115002 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000183

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000952

Gnomad ASJ AF: 0.00104

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000974

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00214

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000994 AC: 249 AN: 250602 AF XY: 0.00103

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.000895

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000699

Gnomad NFE exome AF: 0.00186

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.00117 AC: 1701 AN: 1457766 Hom.: 1 Cov.: 29 AF XY: 0.00119 AC XY: 863 AN XY: 725496

African (AFR) AF: 0.000180 AC: 6 AN: 33368

American (AMR) AF: 0.000112 AC: 5 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.000997 AC: 26 AN: 26080

East Asian (EAS) AF: 0.00 AC: 0 AN: 39660

South Asian (SAS) AF: 0.00 AC: 0 AN: 86172

European-Finnish (FIN) AF: 0.000637 AC: 34 AN: 53364

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5742

European-Non Finnish (NFE) AF: 0.00141 AC: 1562 AN: 1108472

Other (OTH) AF: 0.00113 AC: 68 AN: 60214

GnomAD4 genome AF: 0.00120 AC: 138 AN: 115126 Hom.: 0 Cov.: 32 AF XY: 0.00127 AC XY: 70 AN XY: 55178

African (AFR) AF: 0.000183 AC: 5 AN: 27388

American (AMR) AF: 0.0000950 AC: 1 AN: 10524

Ashkenazi Jewish (ASJ) AF: 0.00104 AC: 3 AN: 2896

East Asian (EAS) AF: 0.00 AC: 0 AN: 4114

South Asian (SAS) AF: 0.00 AC: 0 AN: 3562

European-Finnish (FIN) AF: 0.000974 AC: 7 AN: 7188

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 226

European-Non Finnish (NFE) AF: 0.00214 AC: 122 AN: 56940

Other (OTH) AF: 0.00 AC: 0 AN: 1520

Alfa AF: 0.00128 Hom.: 1

Bravo AF: 0.000839

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	3	not specified (3)
-	-	1	Amyotrophic lateral sclerosis type 11 (1)
-	-	1	Charcot-Marie-Tooth disease (1)
-	-	1	Charcot-Marie-Tooth disease type 4 (1)
-	1	-	Charcot-Marie-Tooth disease type 4J (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	6.9
DANN	Benign	0.76
PhyloP100		0.038
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs190287033; hg19: chr6-110048477;