rs2273752

Variant names:

• chr6-109738307-C-A
• rs2273752
• NM_014845.6:c.647-18C>A

Your query was ambiguous. Multiple possible variants found:

• chr6-109738307-C-A
• chr6-109738307-C-T

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.647-18C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.374 in 1,579,074 control chromosomes in the GnomAD database, including 113,384 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.34 (9275 hom., cov: 32)
  • Exomes 𝑓: 0.38 (104109 hom.)
• Consequence: FIG4 NM_014845.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.200
• Publications: 9 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 -20 ACMG points.

• BP4: This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 1 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 6-109738307-C-A is Benign according to our data. Variant chr6-109738307-C-A is described in ClinVar as Benign. ClinVar VariationId is 260451.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.438 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FIG4	NM_014845.6	MANE Select	c.647-18C>A		intron	N/A	NP_055660.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FIG4	ENST00000230124.8	TSL:1 MANE Select	c.647-18C>A		intron	N/A	ENSP00000230124.4
	FIG4	ENST00000674532.1		n.3825C>A		non_coding_transcript_exon	Exon 6 of 22
	FIG4	ENST00000675272.1		n.1535C>A		non_coding_transcript_exon	Exon 1 of 15

Frequencies

GnomAD3 genomes AF: 0.338 AC: 51244 AN: 151660 Hom.: 9271 Cov.: 32

Gnomad AFR AF: 0.188

Gnomad AMI AF: 0.295

Gnomad AMR AF: 0.407

Gnomad ASJ AF: 0.482

Gnomad EAS AF: 0.402

Gnomad SAS AF: 0.453

Gnomad FIN AF: 0.410

Gnomad MID AF: 0.449

Gnomad NFE AF: 0.381

Gnomad OTH AF: 0.362

GnomAD2 exomes AF: 0.391 AC: 97958 AN: 250508 AF XY: 0.397

Gnomad AFR exome AF: 0.179

Gnomad AMR exome AF: 0.428

Gnomad ASJ exome AF: 0.472

Gnomad EAS exome AF: 0.375

Gnomad FIN exome AF: 0.417

Gnomad NFE exome AF: 0.384

Gnomad OTH exome AF: 0.406

GnomAD4 exome AF: 0.378 AC: 539988 AN: 1427296 Hom.: 104109 Cov.: 28 AF XY: 0.382 AC XY: 271824 AN XY: 711978

African (AFR) AF: 0.179 AC: 5889 AN: 32968

American (AMR) AF: 0.427 AC: 19001 AN: 44546

Ashkenazi Jewish (ASJ) AF: 0.471 AC: 12170 AN: 25832

East Asian (EAS) AF: 0.420 AC: 16566 AN: 39454

South Asian (SAS) AF: 0.444 AC: 37917 AN: 85446

European-Finnish (FIN) AF: 0.416 AC: 22181 AN: 53280

Middle Eastern (MID) AF: 0.414 AC: 2350 AN: 5678

European-Non Finnish (NFE) AF: 0.371 AC: 401326 AN: 1080924

Other (OTH) AF: 0.382 AC: 22588 AN: 59168

GnomAD4 genome AF: 0.338 AC: 51273 AN: 151778 Hom.: 9275 Cov.: 32 AF XY: 0.342 AC XY: 25335 AN XY: 74174

African (AFR) AF: 0.188 AC: 7791 AN: 41398

American (AMR) AF: 0.407 AC: 6202 AN: 15234

Ashkenazi Jewish (ASJ) AF: 0.482 AC: 1674 AN: 3470

East Asian (EAS) AF: 0.402 AC: 2070 AN: 5146

South Asian (SAS) AF: 0.454 AC: 2185 AN: 4816

European-Finnish (FIN) AF: 0.410 AC: 4308 AN: 10510

Middle Eastern (MID) AF: 0.446 AC: 131 AN: 294

European-Non Finnish (NFE) AF: 0.381 AC: 25882 AN: 67904

Other (OTH) AF: 0.363 AC: 763 AN: 2100

Alfa AF: 0.361 Hom.: 2342

Bravo AF: 0.332

Asia WGS AF: 0.422 AC: 1465 AN: 3476

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	1	Charcot-Marie-Tooth disease (1)
-	-	1	Charcot-Marie-Tooth disease type 4 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	12
DANN	Benign	0.79
PhyloP100		-0.20
BranchPoint Hunter		1.0
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: rs2273752; hg19: chr6-110059510; COSMIC: COSV57790518;