rs1127771

Variant names:

• chr6-109825100-G-A
• rs1127771
• NM_014845.6:c.2559G>A

Your query was ambiguous. Multiple possible variants found:

• chr6-109825100-G-A
• chr6-109825100-G-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_014845.6(FIG4):​c.2559G>A​(p.Ser853Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.416 in 1,611,466 control chromosomes in the GnomAD database, including 144,488 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. S853S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.36 (11207 hom., cov: 32)
  • Exomes 𝑓: 0.42 (133281 hom.)
• Consequence: FIG4 NM_014845.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: -2.65
• Publications: 19 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 6-109825100-G-A is Benign according to our data. Variant chr6-109825100-G-A is described in ClinVar as Benign. ClinVar VariationId is 260449.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.65 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.573 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.2559G>A	p.Ser853Ser	synonymous	Exon 23 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.2559G>A	p.Ser853Ser	synonymous	Exon 23 of 23	ENSP00000230124.4	Q92562
	FIG4	ENST00000674884.1		c.2577G>A	p.Ser859Ser	synonymous	Exon 23 of 23	ENSP00000502668.1	A0A6Q8PHH5
	FIG4	ENST00000674744.1		c.2553G>A	p.Ser851Ser	synonymous	Exon 23 of 23	ENSP00000501661.1	A0A6Q8PF62

Frequencies

GnomAD3 genomes AF: 0.359 AC: 54508 AN: 151896 Hom.: 11209 Cov.: 32

Gnomad AFR AF: 0.149

Gnomad AMI AF: 0.384

Gnomad AMR AF: 0.476

Gnomad ASJ AF: 0.489

Gnomad EAS AF: 0.590

Gnomad SAS AF: 0.551

Gnomad FIN AF: 0.411

Gnomad MID AF: 0.503

Gnomad NFE AF: 0.412

Gnomad OTH AF: 0.401

GnomAD2 exomes AF: 0.439 AC: 110072 AN: 250872 AF XY: 0.447

Gnomad AFR exome AF: 0.139

Gnomad AMR exome AF: 0.495

Gnomad ASJ exome AF: 0.483

Gnomad EAS exome AF: 0.575

Gnomad FIN exome AF: 0.422

Gnomad NFE exome AF: 0.411

Gnomad OTH exome AF: 0.454

GnomAD4 exome AF: 0.422 AC: 615174 AN: 1459452 Hom.: 133281 Cov.: 35 AF XY: 0.426 AC XY: 309595 AN XY: 726214

African (AFR) AF: 0.138 AC: 4634 AN: 33466

American (AMR) AF: 0.495 AC: 22153 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.483 AC: 12625 AN: 26116

East Asian (EAS) AF: 0.566 AC: 22469 AN: 39674

South Asian (SAS) AF: 0.548 AC: 47263 AN: 86202

European-Finnish (FIN) AF: 0.420 AC: 22428 AN: 53392

Middle Eastern (MID) AF: 0.458 AC: 2639 AN: 5760

European-Non Finnish (NFE) AF: 0.410 AC: 454598 AN: 1109812

Other (OTH) AF: 0.437 AC: 26365 AN: 60306

GnomAD4 genome AF: 0.359 AC: 54514 AN: 152014 Hom.: 11207 Cov.: 32 AF XY: 0.366 AC XY: 27153 AN XY: 74280

African (AFR) AF: 0.149 AC: 6158 AN: 41454

American (AMR) AF: 0.476 AC: 7265 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.489 AC: 1697 AN: 3472

East Asian (EAS) AF: 0.591 AC: 3053 AN: 5170

South Asian (SAS) AF: 0.550 AC: 2650 AN: 4816

European-Finnish (FIN) AF: 0.411 AC: 4342 AN: 10558

Middle Eastern (MID) AF: 0.497 AC: 146 AN: 294

European-Non Finnish (NFE) AF: 0.412 AC: 28004 AN: 67972

Other (OTH) AF: 0.404 AC: 849 AN: 2104

Alfa AF: 0.394 Hom.: 32383

Bravo AF: 0.352

Asia WGS AF: 0.550 AC: 1909 AN: 3478

EpiCase AF: 0.432

EpiControl AF: 0.434

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	2	Amyotrophic lateral sclerosis type 11 (2)
-	-	2	Charcot-Marie-Tooth disease type 4J (2)
-	-	1	Bilateral parasagittal parieto-occipital polymicrogyria (1)
-	-	1	Charcot-Marie-Tooth disease (1)
-	-	1	Charcot-Marie-Tooth disease type 4 (1)
-	-	1	not provided (1)
-	-	1	Yunis-Varon syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	0.17
DANN	Benign	0.75
PhyloP100		-2.6
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1127771; hg19: chr6-110146303; COSMIC: COSV57786296; COSMIC: COSV57786296;