chr12-32502338-G-C

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 0 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 -15 ACMG points.

• PP3: Splicing predictors support a deleterious 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 VariationId is 308281.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0979 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_139241.3. 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.167-61799G>C		intron	N/A	NP_001357227.2	F8VWL3
	FGD4	NM_139241.3		c.-246G>C		splice_region	Exon 1 of 17	NP_640334.2	Q96M96-1
	FGD4	NM_001384127.1		c.-246G>C		splice_region	Exon 1 of 18	NP_001371056.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FGD4	ENST00000534526.7	TSL:5 MANE Select	c.167-61799G>C		intron	N/A	ENSP00000449273.1	F8VWL3
	FGD4	ENST00000395740.5	TSL:1	n.-246G>C		splice_region non_coding_transcript_exon	Exon 1 of 17	ENSP00000379089.1	E9PNX0
	FGD4	ENST00000494275.5	TSL:1	n.290G>C		splice_region non_coding_transcript_exon	Exon 1 of 3

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

African (AFR) AF: 0.00215 AC: 34 AN: 15786

American (AMR) AF: 0.101 AC: 99 AN: 984

Ashkenazi Jewish (ASJ) AF: 0.00272 AC: 14 AN: 5152

East Asian (EAS) AF: 0.0408 AC: 148 AN: 3630

South Asian (SAS) AF: 0.0213 AC: 350 AN: 16460

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 276

Middle Eastern (MID) AF: 0.000617 AC: 1 AN: 1620

European-Non Finnish (NFE) AF: 0.000180 AC: 137 AN: 761888

Other (OTH) AF: 0.00528 AC: 144 AN: 27298

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

African (AFR) AF: 0.00378 AC: 157 AN: 41552

American (AMR) AF: 0.102 AC: 1560 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00461 AC: 16 AN: 3472

East Asian (EAS) AF: 0.0516 AC: 267 AN: 5178

South Asian (SAS) AF: 0.0230 AC: 111 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000617 AC: 42 AN: 68034

Other (OTH) AF: 0.0152 AC: 32 AN: 2112

Alfa AF: 0.00715 Hom.: 11

Bravo AF: 0.0220

Asia WGS AF: 0.0430 AC: 148 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Charcot-Marie-Tooth disease type 4H (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	22
DANN	Benign	0.95
PhyloP100		5.8
PromoterAI		-0.22	Neutral
Mutation Taster		=293/7	polymorphism (auto)

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

Other links and lift over

dbSNP: rs77113168; hg19: chr12-32655272;