rs60803891

Positions:

• chr12-32624425-T-C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001370298.3(FGD4):​c.1926T>C​(p.Ser642=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00288 in 1,601,258 control chromosomes in the GnomAD database, including 99 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (51 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (48 hom.)
• Consequence: FGD4 NM_001370298.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 1.81

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]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 12-32624425-T-C is Benign according to our data. Variant chr12-32624425-T-C is described in ClinVar as [Benign]. Clinvar id is 308298.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-32624425-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=1.81 with no splicing effect.
• BA1: GnomAdExome4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0505 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FGD4	NM_001370298.3	c.1926T>C	p.Ser642=	synonymous_variant	12/17	ENST00000534526.7	NP_001357227.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FGD4	ENST00000534526.7	c.1926T>C	p.Ser642=	synonymous_variant	12/17	5	NM_001370298.3	ENSP00000449273

Frequencies

GnomAD3 genomes AF: 0.0150 AC: 2284 AN: 152152 Hom.: 50 Cov.: 32

Gnomad AFR AF: 0.0514

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00701

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.0129

GnomAD3 exomes AF: 0.00383 AC: 948 AN: 247666 Hom.: 28 AF XY: 0.00269 AC XY: 360 AN XY: 133920

Gnomad AFR exome AF: 0.0506

Gnomad AMR exome AF: 0.00309

Gnomad ASJ exome AF: 0.000101

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000166

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000170

Gnomad OTH exome AF: 0.00132

GnomAD4 exome AF: 0.00160 AC: 2322 AN: 1448990 Hom.: 48 Cov.: 28 AF XY: 0.00138 AC XY: 998 AN XY: 721128

Gnomad4 AFR exome AF: 0.0525

Gnomad4 AMR exome AF: 0.00321

Gnomad4 ASJ exome AF: 0.0000386

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000936

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000162

Gnomad4 OTH exome AF: 0.00372

GnomAD4 genome AF: 0.0151 AC: 2293 AN: 152268 Hom.: 51 Cov.: 32 AF XY: 0.0150 AC XY: 1115 AN XY: 74452

Gnomad4 AFR AF: 0.0515

Gnomad4 AMR AF: 0.00700

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000265

Gnomad4 OTH AF: 0.0128

Alfa AF: 0.00762 Hom.: 11

Bravo AF: 0.0172

Asia WGS AF: 0.00693 AC: 24 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Charcot-Marie-Tooth disease type 4H Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 22, 2023	- -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 30, 2018	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 25, 2015

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Charcot-Marie-Tooth disease Benign:1

Benign, criteria provided, single submitter

clinical testing

Molecular Genetics Laboratory, London Health Sciences Centre

-

- -

FGD4-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 04, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Charcot-Marie-Tooth disease type 4 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 27, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	10
DANN	Benign	0.76

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

Publications

LitVar

Other links and lift over

dbSNP: rs60803891; hg19: chr12-32777359;