NM_001370298.3:c.2047-7T>C

Variant names:

• chr12-32625647-T-C
• rs11052113
• NM_001370298.3:c.2047-7T>C

Variant summary

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

The NM_001370298.3(FGD4):​c.2047-7T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.137 in 1,613,064 control chromosomes in the GnomAD database, including 16,562 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (1998 hom., cov: 31)
  • Exomes 𝑓: 0.14 (14564 hom.)
• Consequence: FGD4 NM_001370298.3 splice_region, intron
• Scores: Splicing: ADA: 0.00001228
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.674
• Publications: 8 publications found

Genes affected

FGD4 (HGNC:19125): (FYVE, RhoGEF and PH domain containing 4) This gene encodes a protein that is involved in the regulation of the actin cytoskeleton and cell shape. This protein contains an actin filament-binding domain, which together with its Dbl homology domain and one of its pleckstrin homology domains, can form microspikes. This protein can activate MAPK8 independently of the actin filament-binding domain, and it is also involved in the activation of CDC42 via the exchange of bound GDP for free GTP. The activation of CDC42 also enables this protein to play a role in mediating the cellular invasion of Cryptosporidium parvum, an intracellular parasite that infects the gastrointestinal tract. Mutations in this gene can cause Charcot-Marie-Tooth disease type 4H (CMT4H), a disorder of the peripheral nervous system. Multiple alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2015]

FGD4 Gene-Disease associations (from GenCC):

• Charcot-Marie-Tooth disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Charcot-Marie-Tooth disease type 4H

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 12-32625647-T-C is Benign according to our data. Variant chr12-32625647-T-C is described in ClinVar as Benign. ClinVar VariationId is 308299.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.222 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGD4	NM_001370298.3	c.2047-7T>C		splice_region_variant, intron_variant	Intron 13 of 16	ENST00000534526.7	NP_001357227.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FGD4	ENST00000534526.7	c.2047-7T>C		splice_region_variant, intron_variant	Intron 13 of 16	5	NM_001370298.3	ENSP00000449273.1

Frequencies

GnomAD3 genomes AF: 0.151 AC: 22880 AN: 151946 Hom.: 1989 Cov.: 31

Gnomad AFR AF: 0.226

Gnomad AMI AF: 0.0967

Gnomad AMR AF: 0.165

Gnomad ASJ AF: 0.0954

Gnomad EAS AF: 0.0131

Gnomad SAS AF: 0.120

Gnomad FIN AF: 0.0550

Gnomad MID AF: 0.259

Gnomad NFE AF: 0.133

Gnomad OTH AF: 0.147

GnomAD2 exomes AF: 0.131 AC: 33023 AN: 251208 AF XY: 0.127

Gnomad AFR exome AF: 0.224

Gnomad AMR exome AF: 0.221

Gnomad ASJ exome AF: 0.0981

Gnomad EAS exome AF: 0.0107

Gnomad FIN exome AF: 0.0582

Gnomad NFE exome AF: 0.127

Gnomad OTH exome AF: 0.140

GnomAD4 exome AF: 0.135 AC: 197816 AN: 1461000 Hom.: 14564 Cov.: 32 AF XY: 0.134 AC XY: 97396 AN XY: 726848

African (AFR) AF: 0.233 AC: 7812 AN: 33470

American (AMR) AF: 0.216 AC: 9643 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.101 AC: 2635 AN: 26116

East Asian (EAS) AF: 0.0121 AC: 482 AN: 39676

South Asian (SAS) AF: 0.131 AC: 11289 AN: 86208

European-Finnish (FIN) AF: 0.0609 AC: 3251 AN: 53384

Middle Eastern (MID) AF: 0.218 AC: 1260 AN: 5768

European-Non Finnish (NFE) AF: 0.138 AC: 153013 AN: 1111330

Other (OTH) AF: 0.140 AC: 8431 AN: 60342

GnomAD4 genome AF: 0.151 AC: 22915 AN: 152064 Hom.: 1998 Cov.: 31 AF XY: 0.146 AC XY: 10869 AN XY: 74354

African (AFR) AF: 0.225 AC: 9341 AN: 41430

American (AMR) AF: 0.165 AC: 2520 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.0954 AC: 331 AN: 3468

East Asian (EAS) AF: 0.0131 AC: 68 AN: 5186

South Asian (SAS) AF: 0.121 AC: 583 AN: 4816

European-Finnish (FIN) AF: 0.0550 AC: 583 AN: 10606

Middle Eastern (MID) AF: 0.259 AC: 76 AN: 294

European-Non Finnish (NFE) AF: 0.133 AC: 9009 AN: 67984

Other (OTH) AF: 0.149 AC: 316 AN: 2114

Alfa AF: 0.140 Hom.: 1185

Bravo AF: 0.164

Asia WGS AF: 0.103 AC: 360 AN: 3478

EpiCase AF: 0.141

EpiControl AF: 0.134

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

Jul 12, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Charcot-Marie-Tooth disease Benign:1

-

Molecular Genetics Laboratory, London Health Sciences Centre

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Charcot-Marie-Tooth disease type 4H Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Charcot-Marie-Tooth disease type 4 Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	2.1
DANN	Benign	0.56
PhyloP100		-0.67
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000012
dbscSNV1_RF	Benign	0.0
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: rs11052113; hg19: chr12-32778581;