rs6914322

Variant names:

• chr6-109785538-A-T
• rs6914322
• NM_014845.6:c.1948+510A>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_014845.6(FIG4):​c.1948+510A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.298 in 305,294 control chromosomes in the GnomAD database, including 19,732 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.34 (12683 hom., cov: 33)
  • Exomes 𝑓: 0.26 (7049 hom.)
• Consequence: FIG4 NM_014845.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.345
• Publications: 7 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: 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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.682 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FIG4	NM_014845.6	c.1948+510A>T		intron_variant	Intron 17 of 22	ENST00000230124.8	NP_055660.1
FIG4	XM_011536281.4	c.1885+510A>T		intron_variant	Intron 17 of 22		XP_011534583.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FIG4	ENST00000230124.8	c.1948+510A>T		intron_variant	Intron 17 of 22	1	NM_014845.6	ENSP00000230124.4

Frequencies

GnomAD3 genomes AF: 0.337 AC: 51281 AN: 151996 Hom.: 12642 Cov.: 33

Gnomad AFR AF: 0.688

Gnomad AMI AF: 0.189

Gnomad AMR AF: 0.278

Gnomad ASJ AF: 0.240

Gnomad EAS AF: 0.405

Gnomad SAS AF: 0.442

Gnomad FIN AF: 0.227

Gnomad MID AF: 0.304

Gnomad NFE AF: 0.150

Gnomad OTH AF: 0.301

GnomAD4 exome AF: 0.259 AC: 39656 AN: 153180 Hom.: 7049 AF XY: 0.273 AC XY: 23248 AN XY: 85032

African (AFR) AF: 0.712 AC: 3361 AN: 4720

American (AMR) AF: 0.277 AC: 2927 AN: 10580

Ashkenazi Jewish (ASJ) AF: 0.265 AC: 957 AN: 3616

East Asian (EAS) AF: 0.399 AC: 2953 AN: 7408

South Asian (SAS) AF: 0.451 AC: 12327 AN: 27306

European-Finnish (FIN) AF: 0.222 AC: 4029 AN: 18184

Middle Eastern (MID) AF: 0.291 AC: 599 AN: 2056

European-Non Finnish (NFE) AF: 0.149 AC: 10835 AN: 72724

Other (OTH) AF: 0.253 AC: 1668 AN: 6586

GnomAD4 genome AF: 0.338 AC: 51391 AN: 152114 Hom.: 12683 Cov.: 33 AF XY: 0.342 AC XY: 25440 AN XY: 74364

African (AFR) AF: 0.689 AC: 28565 AN: 41484

American (AMR) AF: 0.279 AC: 4259 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.240 AC: 832 AN: 3468

East Asian (EAS) AF: 0.406 AC: 2096 AN: 5164

South Asian (SAS) AF: 0.441 AC: 2131 AN: 4832

European-Finnish (FIN) AF: 0.227 AC: 2398 AN: 10578

Middle Eastern (MID) AF: 0.303 AC: 89 AN: 294

European-Non Finnish (NFE) AF: 0.150 AC: 10209 AN: 67988

Other (OTH) AF: 0.303 AC: 640 AN: 2110

Alfa AF: 0.262 Hom.: 985

Bravo AF: 0.350

Asia WGS AF: 0.445 AC: 1542 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	5.3
DANN	Benign	0.68
PhyloP100		0.34
Mutation Taster		=100/0	polymorphism (auto)

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: rs6914322; hg19: chr6-110106741; COSMIC: COSV57786157; COSMIC: COSV57786157;