chr6-109786314-T-C

Variant names:

• chr6-109786314-T-C
• rs9885672
• NM_014845.6:c.1961T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_014845.6(FIG4):​c.1961T>C​(p.Val654Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.21 in 1,610,604 control chromosomes in the GnomAD database, including 51,283 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.34 (12744 hom., cov: 32)
  • Exomes 𝑓: 0.20 (38539 hom.)
• Consequence: FIG4 NM_014845.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:18
• Conservation: PhyloP100: 3.51
• Publications: 45 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.9537024E-6).
• BP6: Variant 6-109786314-T-C is Benign according to our data. Variant chr6-109786314-T-C is described in ClinVar as Benign. ClinVar VariationId is 137377.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.683 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.1961T>C	p.Val654Ala	missense	Exon 18 of 23	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.1961T>C	p.Val654Ala	missense	Exon 18 of 23	ENSP00000230124.4	Q92562
	FIG4	ENST00000674884.1		c.1979T>C	p.Val660Ala	missense	Exon 18 of 23	ENSP00000502668.1	A0A6Q8PHH5
	FIG4	ENST00000674744.1		c.1955T>C	p.Val652Ala	missense	Exon 18 of 23	ENSP00000501661.1	A0A6Q8PF62

Frequencies

GnomAD3 genomes AF: 0.338 AC: 51380 AN: 151966 Hom.: 12703 Cov.: 32

Gnomad AFR AF: 0.689

Gnomad AMI AF: 0.188

Gnomad AMR AF: 0.278

Gnomad ASJ AF: 0.240

Gnomad EAS AF: 0.416

Gnomad SAS AF: 0.443

Gnomad FIN AF: 0.227

Gnomad MID AF: 0.304

Gnomad NFE AF: 0.150

Gnomad OTH AF: 0.302

GnomAD2 exomes AF: 0.269 AC: 67455 AN: 251048 AF XY: 0.266

Gnomad AFR exome AF: 0.695

Gnomad AMR exome AF: 0.271

Gnomad ASJ exome AF: 0.252

Gnomad EAS exome AF: 0.406

Gnomad FIN exome AF: 0.223

Gnomad NFE exome AF: 0.150

Gnomad OTH exome AF: 0.226

GnomAD4 exome AF: 0.197 AC: 287471 AN: 1458520 Hom.: 38539 Cov.: 30 AF XY: 0.203 AC XY: 147061 AN XY: 725726

African (AFR) AF: 0.710 AC: 23661 AN: 33330

American (AMR) AF: 0.270 AC: 12089 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.248 AC: 6467 AN: 26088

East Asian (EAS) AF: 0.397 AC: 15728 AN: 39656

South Asian (SAS) AF: 0.441 AC: 37986 AN: 86136

European-Finnish (FIN) AF: 0.217 AC: 11599 AN: 53374

Middle Eastern (MID) AF: 0.313 AC: 1800 AN: 5758

European-Non Finnish (NFE) AF: 0.147 AC: 163285 AN: 1109220

Other (OTH) AF: 0.247 AC: 14856 AN: 60260

GnomAD4 genome AF: 0.339 AC: 51488 AN: 152084 Hom.: 12744 Cov.: 32 AF XY: 0.343 AC XY: 25497 AN XY: 74360

African (AFR) AF: 0.690 AC: 28605 AN: 41462

American (AMR) AF: 0.278 AC: 4251 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.240 AC: 833 AN: 3472

East Asian (EAS) AF: 0.417 AC: 2152 AN: 5166

South Asian (SAS) AF: 0.442 AC: 2132 AN: 4822

European-Finnish (FIN) AF: 0.227 AC: 2407 AN: 10594

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

European-Non Finnish (NFE) AF: 0.150 AC: 10204 AN: 67990

Other (OTH) AF: 0.305 AC: 644 AN: 2112

Alfa AF: 0.209 Hom.: 24727

Bravo AF: 0.351

TwinsUK AF: 0.147 AC: 546

ALSPAC AF: 0.141 AC: 542

ESP6500AA AF: 0.668 AC: 2945

ESP6500EA AF: 0.152 AC: 1304

ExAC AF: 0.275 AC: 33396

Asia WGS AF: 0.455 AC: 1578 AN: 3478

EpiCase AF: 0.160

EpiControl AF: 0.161

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	3	Amyotrophic lateral sclerosis type 11 (3)
-	-	2	Charcot-Marie-Tooth disease type 4J (2)
-	-	2	not provided (2)
-	-	1	Bilateral parasagittal parieto-occipital polymicrogyria (1)
-	-	1	Charcot-Marie-Tooth disease (1)
-	-	1	Charcot-Marie-Tooth disease type 4 (1)
-	-	1	Yunis-Varon syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.053
BayesDel_addAF	Benign	-0.75	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	11
DANN	Benign	0.56
DEOGEN2	Benign	0.17	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-0.95
FATHMM_MKL	Benign	0.65	D
LIST_S2	Benign	0.015	T
MetaRNN	Benign	0.0000019	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.0	N
PhyloP100		3.5
PrimateAI	Benign	0.28	T
PROVEAN	Benign	0.95	N
REVEL	Benign	0.068
Sift	Benign	0.83	T
Sift4G	Benign	0.75	T
Polyphen		0.0	B
Vest4		0.024
MPC		0.37
ClinPred		0.0017	T
GERP RS		1.3
Varity_R		0.020
gMVP		0.21
Mutation Taster		=99/1	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: rs9885672; hg19: chr6-110107517; COSMIC: COSV57786166; COSMIC: COSV57786166;