rs73305543

Variant names:

• chr12-32563911-G-A
• rs73305543
• NM_001370298.3:c.167-226G>A

Your query was ambiguous. Multiple possible variants found:

• chr12-32563911-G-A
• chr12-32563911-G-C
• chr12-32563911-G-T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001370298.3(FGD4):​c.167-226G>A variant causes a intron change. The variant allele was found at a frequency of 0.094 in 151,778 control chromosomes in the GnomAD database, including 1,049 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.094 (1049 hom., cov: 29)
• Consequence: FGD4 NM_001370298.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: No conservation score assigned
• 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BP6: Variant 12-32563911-G-A is Benign according to our data. Variant chr12-32563911-G-A is described in ClinVar as Benign. ClinVar VariationId is 1293247.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.199 is higher than 0.05.

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.167-226G>A		intron	N/A	NP_001357227.2	F8VWL3
	FGD4	NM_001384126.1		c.167-226G>A		intron	N/A	NP_001371055.1
	FGD4	NM_001304481.2		c.11-226G>A		intron	N/A	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.167-226G>A		intron	N/A	ENSP00000449273.1	F8VWL3
	FGD4	ENST00000395740.5	TSL:1	n.-245-226G>A		intron	N/A	ENSP00000379089.1	E9PNX0
	FGD4	ENST00000494275.5	TSL:1	n.291-226G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0938 AC: 14232 AN: 151658 Hom.: 1043 Cov.: 29

Gnomad AFR AF: 0.203

Gnomad AMI AF: 0.0724

Gnomad AMR AF: 0.0639

Gnomad ASJ AF: 0.0905

Gnomad EAS AF: 0.0319

Gnomad SAS AF: 0.0459

Gnomad FIN AF: 0.0314

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.0531

Gnomad OTH AF: 0.0888

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0940 AC: 14261 AN: 151778 Hom.: 1049 Cov.: 29 AF XY: 0.0909 AC XY: 6741 AN XY: 74142

African (AFR) AF: 0.203 AC: 8383 AN: 41300

American (AMR) AF: 0.0636 AC: 969 AN: 15240

Ashkenazi Jewish (ASJ) AF: 0.0905 AC: 314 AN: 3468

East Asian (EAS) AF: 0.0320 AC: 164 AN: 5132

South Asian (SAS) AF: 0.0459 AC: 221 AN: 4816

European-Finnish (FIN) AF: 0.0314 AC: 331 AN: 10536

Middle Eastern (MID) AF: 0.0612 AC: 18 AN: 294

European-Non Finnish (NFE) AF: 0.0531 AC: 3612 AN: 67974

Other (OTH) AF: 0.0869 AC: 183 AN: 2106

Alfa AF: 0.0762 Hom.: 80

Bravo AF: 0.101

Asia WGS AF: 0.0430 AC: 150 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	3.2
DANN	Benign	0.93
Mutation Taster		=100/0	polymorphism (auto)

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: rs73305543; hg19: chr12-32716845;