12-32502338-G-C

Variant names:

• chr12-32502338-G-C
• rs77113168
• NM_001370298.3:c.167-61799G>C

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP3 BP6_Very_Strong BA1

The NM_139241.3(FGD4):​c.-246G>C variant causes a splice region change. The variant allele was found at a frequency of 0.00316 in 985,358 control chromosomes in the GnomAD database, including 134 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (121 hom., cov: 33)
  • Exomes 𝑓: 0.0011 (13 hom.)
• Consequence: FGD4 NM_139241.3 splice_region
• Scores: Splicing: ADA: 0.9585
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 5.83

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 -15 ACMG points.

• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• BP6: Variant 12-32502338-G-C is Benign according to our data. Variant chr12-32502338-G-C is described in ClinVar as [Benign]. Clinvar id is 308281.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-32502338-G-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0979 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGD4	NM_001370298.3	c.167-61799G>C		intron_variant	Intron 1 of 16	ENST00000534526.7	NP_001357227.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FGD4	ENST00000534526.7	c.167-61799G>C		intron_variant	Intron 1 of 16	5	NM_001370298.3	ENSP00000449273.1

Frequencies

GnomAD3 genomes AF: 0.0143 AC: 2173 AN: 152148 Hom.: 116 Cov.: 33

Gnomad AFR AF: 0.00379

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.102

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.0511

Gnomad SAS AF: 0.0228

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000617

Gnomad OTH AF: 0.0153

GnomAD4 exome AF: 0.00111 AC: 927 AN: 833094 Hom.: 13 Cov.: 29 AF XY: 0.00107 AC XY: 410 AN XY: 384710

Gnomad4 AFR exome AF: 0.00215

Gnomad4 AMR exome AF: 0.101

Gnomad4 ASJ exome AF: 0.00272

Gnomad4 EAS exome AF: 0.0408

Gnomad4 SAS exome AF: 0.0213

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000180

Gnomad4 OTH exome AF: 0.00528

GnomAD4 genome AF: 0.0144 AC: 2185 AN: 152264 Hom.: 121 Cov.: 33 AF XY: 0.0167 AC XY: 1241 AN XY: 74442

Gnomad4 AFR AF: 0.00378

Gnomad4 AMR AF: 0.102

Gnomad4 ASJ AF: 0.00461

Gnomad4 EAS AF: 0.0516

Gnomad4 SAS AF: 0.0230

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000617

Gnomad4 OTH AF: 0.0152

Alfa AF: 0.00715 Hom.: 11

Bravo AF: 0.0220

Asia WGS AF: 0.0430 AC: 148 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Jan 13, 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. -

not provided Benign:1

Mar 03, 2015

GeneDx

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	-0.46
CADD	Benign	22
DANN	Benign	0.95

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.96
dbscSNV1_RF	Pathogenic	0.80
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: rs77113168; hg19: chr12-32655272;