chr12-32399835-C-G

Position:

• chr12-32399835-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001370298.3(FGD4):​c.42C>G​(p.Ile14Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.359 in 1,530,910 control chromosomes in the GnomAD database, including 104,664 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/12 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.45 (16856 hom., cov: 33)
  • Exomes 𝑓: 0.35 (87808 hom.)
• Consequence: FGD4 NM_001370298.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.60

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=7.276982E-6).
• BP6: Variant 12-32399835-C-G is Benign according to our data. Variant chr12-32399835-C-G is described in ClinVar as [Benign]. Clinvar id is 802832.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.657 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FGD4	NM_001370298.3	c.42C>G	p.Ile14Met	missense_variant	1/17	ENST00000534526.7	NP_001357227.2
FGD4	NM_001384126.1	c.42C>G	p.Ile14Met	missense_variant	1/18		NP_001371055.1
FGD4	XR_001748576.2	n.278C>G		non_coding_transcript_exon_variant	1/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FGD4	ENST00000534526.7	c.42C>G	p.Ile14Met	missense_variant	1/17	5	NM_001370298.3	ENSP00000449273
FGD4	ENST00000550091.5			upstream_gene_variant		4

Frequencies

GnomAD3 genomes AF: 0.448 AC: 68056 AN: 151924 Hom.: 16817 Cov.: 33

Gnomad AFR AF: 0.663

Gnomad AMI AF: 0.365

Gnomad AMR AF: 0.386

Gnomad ASJ AF: 0.309

Gnomad EAS AF: 0.526

Gnomad SAS AF: 0.392

Gnomad FIN AF: 0.441

Gnomad MID AF: 0.266

Gnomad NFE AF: 0.340

Gnomad OTH AF: 0.411

GnomAD3 exomes AF: 0.384 AC: 47717 AN: 124180 Hom.: 9723 AF XY: 0.378 AC XY: 25811 AN XY: 68218

Gnomad AFR exome AF: 0.668

Gnomad AMR exome AF: 0.398

Gnomad ASJ exome AF: 0.310

Gnomad EAS exome AF: 0.511

Gnomad SAS exome AF: 0.375

Gnomad FIN exome AF: 0.443

Gnomad NFE exome AF: 0.332

Gnomad OTH exome AF: 0.356

GnomAD4 exome AF: 0.350 AC: 481934 AN: 1378868 Hom.: 87808 Cov.: 50 AF XY: 0.349 AC XY: 237444 AN XY: 680450

Gnomad4 AFR exome AF: 0.672

Gnomad4 AMR exome AF: 0.392

Gnomad4 ASJ exome AF: 0.313

Gnomad4 EAS exome AF: 0.554

Gnomad4 SAS exome AF: 0.373

Gnomad4 FIN exome AF: 0.444

Gnomad4 NFE exome AF: 0.328

Gnomad4 OTH exome AF: 0.359

GnomAD4 genome AF: 0.448 AC: 68162 AN: 152042 Hom.: 16856 Cov.: 33 AF XY: 0.453 AC XY: 33649 AN XY: 74324

Gnomad4 AFR AF: 0.663

Gnomad4 AMR AF: 0.386

Gnomad4 ASJ AF: 0.309

Gnomad4 EAS AF: 0.525

Gnomad4 SAS AF: 0.392

Gnomad4 FIN AF: 0.441

Gnomad4 NFE AF: 0.340

Gnomad4 OTH AF: 0.417

Alfa AF: 0.387 Hom.: 2455

Bravo AF: 0.456

TwinsUK AF: 0.310 AC: 1150

ALSPAC AF: 0.306 AC: 1179

ExAC AF: 0.330 AC: 4199

Asia WGS AF: 0.495 AC: 1718 AN: 3470

ClinVar

Significance: Benign

Submissions summary: Benign:3

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	Genome-Nilou Lab	Aug 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	16
DANN	Benign	0.83
DEOGEN2	Benign	0.013	T
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.56
FATHMM_MKL	Benign	0.052	N
LIST_S2	Benign	0.52	T
MetaRNN	Benign	0.0000073	T
MetaSVM	Benign	-0.93	T
MutationTaster	Benign	1.0	P
PROVEAN	Benign	-0.060	N
REVEL	Benign	0.088
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.15	T
Vest4		0.12
ClinPred		0.088	T
GERP RS		-0.77

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs2651369; hg19: chr12-32552769; COSMIC: COSV65941651; COSMIC: COSV65941651;