rs9481003

chr6-109760415-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_014845.6(FIG4):c.1271+32G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0753 in 1,589,434 control chromosomes in the GnomAD database, including 10,731 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.16 (3699 hom., cov: 32)
  • Exomes 𝑓: 0.066 (7032 hom.)
• Consequence: FIG4 NM_014845.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.14

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 6-109760415-G-A is Benign according to our data. Variant chr6-109760415-G-A is described in ClinVar as [Benign]. Clinvar id is 260445.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.382 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FIG4	NM_014845.6	c.1271+32G>A		intron_variant		ENST00000230124.8
FIG4	XM_011536281.4	c.1208+32G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FIG4	ENST00000230124.8	c.1271+32G>A		intron_variant		1	NM_014845.6	P4

Frequencies

GnomAD3 genomes AF: 0.163 AC: 24786 AN: 151862 Hom.: 3690 Cov.: 32

Gnomad AFR AF: 0.387

Gnomad AMI AF: 0.110

Gnomad AMR AF: 0.137

Gnomad ASJ AF: 0.126

Gnomad EAS AF: 0.275

Gnomad SAS AF: 0.0941

Gnomad FIN AF: 0.119

Gnomad MID AF: 0.0924

Gnomad NFE AF: 0.0397

Gnomad OTH AF: 0.150

GnomAD3 exomes AF: 0.114 AC: 28519 AN: 250642 Hom.: 2940 AF XY: 0.106 AC XY: 14364 AN XY: 135528

Gnomad AFR exome AF: 0.395

Gnomad AMR exome AF: 0.130

Gnomad ASJ exome AF: 0.130

Gnomad EAS exome AF: 0.295

Gnomad SAS exome AF: 0.107

Gnomad FIN exome AF: 0.113

Gnomad NFE exome AF: 0.0415

Gnomad OTH exome AF: 0.0830

GnomAD4 exome AF: 0.0660 AC: 94827 AN: 1437454 Hom.: 7032 Cov.: 27 AF XY: 0.0663 AC XY: 47519 AN XY: 716804

Gnomad4 AFR exome AF: 0.393

Gnomad4 AMR exome AF: 0.129

Gnomad4 ASJ exome AF: 0.127

Gnomad4 EAS exome AF: 0.296

Gnomad4 SAS exome AF: 0.106

Gnomad4 FIN exome AF: 0.110

Gnomad4 NFE exome AF: 0.0371

Gnomad4 OTH exome AF: 0.0911

GnomAD4 genome AF: 0.163 AC: 24844 AN: 151980 Hom.: 3699 Cov.: 32 AF XY: 0.166 AC XY: 12341 AN XY: 74286

Gnomad4 AFR AF: 0.387

Gnomad4 AMR AF: 0.137

Gnomad4 ASJ AF: 0.126

Gnomad4 EAS AF: 0.276

Gnomad4 SAS AF: 0.0934

Gnomad4 FIN AF: 0.119

Gnomad4 NFE AF: 0.0397

Gnomad4 OTH AF: 0.150

Alfa AF: 0.0641 Hom.: 1359

Bravo AF: 0.175

Asia WGS AF: 0.191 AC: 665 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 26, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
Cadd	Benign	0.051
Dann	Benign	0.38

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: rs9481003; hg19: chr6-110081618; COSMIC: COSV57785924;