chr12-32582103-C-T

Variant names:

• chr12-32582103-C-T
• rs145115430
• NM_001370298.3:c.647C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001370298.3(FGD4):​c.647C>T​(p.Thr216Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000436 in 1,614,154 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0020 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00027 (2 hom.)
• Consequence: FGD4 NM_001370298.3 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 2.38
• Publications: 7 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 (MetaRNN=0.004287809).
• BP6: Variant 12-32582103-C-T is Benign according to our data. Variant chr12-32582103-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 414873.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00202 (308/152260) while in subpopulation AFR AF = 0.00602 (250/41548). AF 95% confidence interval is 0.0054. There are 1 homozygotes in GnomAd4. There are 173 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001370298.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FGD4	NM_001370298.3	MANE Select	c.647C>T	p.Thr216Ile	missense	Exon 4 of 17	NP_001357227.2	F8VWL3
	FGD4	NM_001384126.1		c.647C>T	p.Thr216Ile	missense	Exon 4 of 18	NP_001371055.1
	FGD4	NM_001304481.2		c.491C>T	p.Thr164Ile	missense	Exon 4 of 17	NP_001291410.1	B7Z493

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FGD4	ENST00000534526.7	TSL:5 MANE Select	c.647C>T	p.Thr216Ile	missense	Exon 4 of 17	ENSP00000449273.1	F8VWL3
	FGD4	ENST00000395740.5	TSL:1	n.236C>T		non_coding_transcript_exon	Exon 4 of 17	ENSP00000379089.1	E9PNX0
	FGD4	ENST00000494275.5	TSL:1	n.587C>T		non_coding_transcript_exon	Exon 3 of 3

Frequencies

GnomAD3 genomes AF: 0.00199 AC: 303 AN: 152142 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00591

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00288

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.000712 AC: 179 AN: 251438 AF XY: 0.000537

Gnomad AFR exome AF: 0.00757

Gnomad AMR exome AF: 0.00116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000879

Gnomad OTH exome AF: 0.000815

GnomAD4 exome AF: 0.000270 AC: 395 AN: 1461894 Hom.: 2 Cov.: 30 AF XY: 0.000260 AC XY: 189 AN XY: 727248

African (AFR) AF: 0.00624 AC: 209 AN: 33480

American (AMR) AF: 0.00114 AC: 51 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00329 AC: 19 AN: 5768

European-Non Finnish (NFE) AF: 0.0000701 AC: 78 AN: 1112012

Other (OTH) AF: 0.000596 AC: 36 AN: 60396

GnomAD4 genome AF: 0.00202 AC: 308 AN: 152260 Hom.: 1 Cov.: 32 AF XY: 0.00232 AC XY: 173 AN XY: 74452

African (AFR) AF: 0.00602 AC: 250 AN: 41548

American (AMR) AF: 0.00288 AC: 44 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 68016

Other (OTH) AF: 0.00142 AC: 3 AN: 2116

Alfa AF: 0.000822 Hom.: 1

Bravo AF: 0.00264

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00681 AC: 30

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000782 AC: 95

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000237

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Charcot-Marie-Tooth disease (1)
-	-	1	Charcot-Marie-Tooth disease type 4 (1)
-	-	1	Charcot-Marie-Tooth disease type 4H (1)
-	-	1	FGD4-related disorder (1)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	9.4
DANN	Uncertain	0.98
DEOGEN2	Benign	0.016	T
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.65
FATHMM_MKL	Benign	0.22	N
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.043	D
MetaRNN	Benign	0.0043	T
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	1.7	L
PhyloP100		2.4
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.77	N
REVEL	Benign	0.13
Sift	Uncertain	0.021	D
Sift4G	Benign	0.067	T
Polyphen		0.017	B
Vest4		0.094
MVP		0.80
MPC		0.36
ClinPred		0.021	T
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.11
gMVP		0.19
Mutation Taster		=98/2	polymorphism

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: rs145115430; hg19: chr12-32735037; COSMIC: COSV106083899; COSMIC: COSV106083899;