rs200890189

Positions:

• chr6-109732621-G-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_014845.6(FIG4):​c.447-16G>T variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0068 in 1,015,068 control chromosomes in the GnomAD database, including 33 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0060 (4 hom., cov: 26)
  • Exomes 𝑓: 0.0069 (29 hom.)
• Consequence: FIG4 NM_014845.6 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.161

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 6-109732621-G-T is Benign according to our data. Variant chr6-109732621-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 260450.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-109732621-G-T is described in Lovd as [Benign]. Variant chr6-109732621-G-T is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAd4 at 4 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FIG4	NM_014845.6	c.447-16G>T		splice_polypyrimidine_tract_variant, intron_variant		ENST00000230124.8	NP_055660.1
FIG4	XM_011536281.4	c.384-16G>T		splice_polypyrimidine_tract_variant, intron_variant			XP_011534583.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FIG4	ENST00000230124.8	c.447-16G>T		splice_polypyrimidine_tract_variant, intron_variant		1	NM_014845.6	ENSP00000230124	P4

Frequencies

GnomAD3 genomes AF: 0.00599 AC: 882 AN: 147352 Hom.: 4 Cov.: 26

Gnomad AFR AF: 0.00246

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00542

Gnomad ASJ AF: 0.00756

Gnomad EAS AF: 0.00118

Gnomad SAS AF: 0.00170

Gnomad FIN AF: 0.00417

Gnomad MID AF: 0.00962

Gnomad NFE AF: 0.00915

Gnomad OTH AF: 0.00547

GnomAD4 exome AF: 0.00693 AC: 6017 AN: 867668 Hom.: 29 Cov.: 14 AF XY: 0.00677 AC XY: 3050 AN XY: 450550

Gnomad4 AFR exome AF: 0.00256

Gnomad4 AMR exome AF: 0.00425

Gnomad4 ASJ exome AF: 0.00680

Gnomad4 EAS exome AF: 0.000889

Gnomad4 SAS exome AF: 0.00165

Gnomad4 FIN exome AF: 0.00562

Gnomad4 NFE exome AF: 0.00826

Gnomad4 OTH exome AF: 0.00689

GnomAD4 genome AF: 0.00598 AC: 882 AN: 147400 Hom.: 4 Cov.: 26 AF XY: 0.00574 AC XY: 411 AN XY: 71602

Gnomad4 AFR AF: 0.00246

Gnomad4 AMR AF: 0.00541

Gnomad4 ASJ AF: 0.00756

Gnomad4 EAS AF: 0.00119

Gnomad4 SAS AF: 0.00171

Gnomad4 FIN AF: 0.00417

Gnomad4 NFE AF: 0.00915

Gnomad4 OTH AF: 0.00543

Alfa AF: 0.00394 Hom.: 0

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	FIG4: BS2 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Charcot-Marie-Tooth disease Benign:1

Benign, criteria provided, single submitter

clinical testing

Molecular Genetics Laboratory, London Health Sciences Centre

-

- -

Yunis-Varon syndrome;C1970011:Charcot-Marie-Tooth disease type 4J;C2675491:Amyotrophic lateral sclerosis type 11;C4013648:Bilateral parasagittal parieto-occipital polymicrogyria Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 09, 2022

- -

Charcot-Marie-Tooth disease type 4 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.30
DANN	Benign	0.12

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

LitVar

Other links and lift over

dbSNP: rs200890189; hg19: chr6-110053824;