rs78113393

Variant names:

• chr12-32564077-T-C
• rs78113393
• NM_001370298.3:c.167-60T>C

Your query was ambiguous. Multiple possible variants found:

• chr12-32564077-T-C
• chr12-32564077-T-A

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.167-60T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00124 in 1,458,970 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0065 (9 hom., cov: 32)
  • Exomes 𝑓: 0.00063 (13 hom.)
• Consequence: FGD4 NM_001370298.3 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -3.66
• Publications: 1 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 (BayesDel_noAF=-0.93).
• BP6: Variant 12-32564077-T-C is Benign according to our data. Variant chr12-32564077-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 1187418.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 = 0.00653 (992/151914) while in subpopulation AFR AF = 0.0227 (939/41370). AF 95% confidence interval is 0.0215. There are 9 homozygotes in GnomAd4. There are 445 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 9 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.167-60T>C		intron	N/A	NP_001357227.2	F8VWL3
	FGD4	NM_001384126.1		c.167-60T>C		intron	N/A	NP_001371055.1
	FGD4	NM_001304481.2		c.11-60T>C		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.167-60T>C		intron	N/A	ENSP00000449273.1	F8VWL3
	FGD4	ENST00000395740.5	TSL:1	n.-245-60T>C		intron	N/A	ENSP00000379089.1	E9PNX0
	FGD4	ENST00000494275.5	TSL:1	n.291-60T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00651 AC: 988 AN: 151796 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.0227

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00197

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00526

GnomAD4 exome AF: 0.000627 AC: 820 AN: 1307056 Hom.: 13 AF XY: 0.000574 AC XY: 368 AN XY: 640750

African (AFR) AF: 0.0233 AC: 681 AN: 29268

American (AMR) AF: 0.000846 AC: 25 AN: 29556

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21544

East Asian (EAS) AF: 0.00 AC: 0 AN: 34056

South Asian (SAS) AF: 0.0000717 AC: 5 AN: 69766

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32040

Middle Eastern (MID) AF: 0.000771 AC: 4 AN: 5186

European-Non Finnish (NFE) AF: 0.0000330 AC: 34 AN: 1030926

Other (OTH) AF: 0.00130 AC: 71 AN: 54714

GnomAD4 genome AF: 0.00653 AC: 992 AN: 151914 Hom.: 9 Cov.: 32 AF XY: 0.00599 AC XY: 445 AN XY: 74278

African (AFR) AF: 0.0227 AC: 939 AN: 41370

American (AMR) AF: 0.00196 AC: 30 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5136

South Asian (SAS) AF: 0.000416 AC: 2 AN: 4812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10572

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 67968

Other (OTH) AF: 0.00521 AC: 11 AN: 2112

Alfa AF: 0.00261 Hom.: 0

Bravo AF: 0.00722

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.0090
DANN	Benign	0.42
PhyloP100		-3.7
Mutation Taster		=100/0	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: rs78113393; hg19: chr12-32717011;