12-32564054-T-G

Variant names:

• chr12-32564054-T-G
• rs61926167
• NM_001370298.3:c.167-83T>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001370298.3(FGD4):​c.167-83T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000105 in 1,068,758 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00019 (0 hom., cov: 25)
  • Exomes 𝑓: 0.00010 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: FGD4 NM_001370298.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.895
• Publications: 3 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).

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.167-83T>G		intron	N/A	NP_001357227.2	F8VWL3
	FGD4	NM_001384126.1		c.167-83T>G		intron	N/A	NP_001371055.1
	FGD4	NM_001304481.2		c.11-83T>G		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.167-83T>G		intron	N/A	ENSP00000449273.1	F8VWL3
	FGD4	ENST00000395740.5	TSL:1	n.-245-83T>G		intron	N/A	ENSP00000379089.1	E9PNX0
	FGD4	ENST00000494275.5	TSL:1	n.291-83T>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.000188 AC: 25 AN: 132774 Hom.: 0 Cov.: 25

Gnomad AFR AF: 0.000152

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000220

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000231

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000174

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000105 AC: 112 AN: 1068758 Hom.: 0 AF XY: 0.000121 AC XY: 63 AN XY: 522778

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000454 AC: 1 AN: 22026

American (AMR) AF: 0.000216 AC: 5 AN: 23156

Ashkenazi Jewish (ASJ) AF: 0.0000570 AC: 1 AN: 17556

East Asian (EAS) AF: 0.000242 AC: 7 AN: 28946

South Asian (SAS) AF: 0.000516 AC: 26 AN: 50434

European-Finnish (FIN) AF: 0.000108 AC: 3 AN: 27676

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3548

European-Non Finnish (NFE) AF: 0.0000741 AC: 63 AN: 849982

Other (OTH) AF: 0.000132 AC: 6 AN: 45434

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000188 AC: 25 AN: 132848 Hom.: 0 Cov.: 25 AF XY: 0.000218 AC XY: 14 AN XY: 64176

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000151 AC: 5 AN: 33038

American (AMR) AF: 0.000458 AC: 6 AN: 13112

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3252

East Asian (EAS) AF: 0.000221 AC: 1 AN: 4532

South Asian (SAS) AF: 0.00 AC: 0 AN: 4080

European-Finnish (FIN) AF: 0.000231 AC: 2 AN: 8660

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 270

European-Non Finnish (NFE) AF: 0.000174 AC: 11 AN: 63230

Other (OTH) AF: 0.00 AC: 0 AN: 1804

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 36

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	2.4
DANN	Benign	0.17
PhyloP100		-0.90

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: rs61926167; hg19: chr12-32716988; COSMIC: COSV56789722;