12-32624993-C-T

Variant names:

• chr12-32624993-C-T
• rs61748364
• NM_001370298.3:c.1971C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_001370298.3(FGD4):​c.1971C>T​(p.Ile657Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00846 in 1,613,006 control chromosomes in the GnomAD database, including 74 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. I657I) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0054 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0088 (71 hom.)
• Consequence: FGD4 NM_001370298.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.0640
• Publications: 5 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: Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.29).
• BP6: Variant 12-32624993-C-T is Benign according to our data. Variant chr12-32624993-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 194280.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.064 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00541 (824/152280) while in subpopulation NFE AF = 0.00891 (606/68028). AF 95% confidence interval is 0.00832. There are 3 homozygotes in GnomAd4. There are 389 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 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.1971C>T	p.Ile657Ile	synonymous	Exon 13 of 17	NP_001357227.2	F8VWL3
	FGD4	NM_001384126.1		c.1971C>T	p.Ile657Ile	synonymous	Exon 13 of 18	NP_001371055.1
	FGD4	NM_001304481.2		c.1815C>T	p.Ile605Ile	synonymous	Exon 13 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.1971C>T	p.Ile657Ile	synonymous	Exon 13 of 17	ENSP00000449273.1	F8VWL3
	FGD4	ENST00000395740.5	TSL:1	n.*952C>T		non_coding_transcript_exon	Exon 14 of 17	ENSP00000379089.1	E9PNX0
	FGD4	ENST00000395740.5	TSL:1	n.*952C>T		3_prime_UTR	Exon 14 of 17	ENSP00000379089.1	E9PNX0

Frequencies

GnomAD3 genomes AF: 0.00543 AC: 826 AN: 152162 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00171

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00210

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00683

Gnomad FIN AF: 0.00622

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00891

Gnomad OTH AF: 0.00525

GnomAD2 exomes AF: 0.00620 AC: 1559 AN: 251410 AF XY: 0.00659

Gnomad AFR exome AF: 0.00154

Gnomad AMR exome AF: 0.00205

Gnomad ASJ exome AF: 0.000992

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00637

Gnomad NFE exome AF: 0.00931

Gnomad OTH exome AF: 0.00587

GnomAD4 exome AF: 0.00878 AC: 12819 AN: 1460726 Hom.: 71 Cov.: 31 AF XY: 0.00871 AC XY: 6333 AN XY: 726694

African (AFR) AF: 0.00114 AC: 38 AN: 33448

American (AMR) AF: 0.00217 AC: 97 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.000460 AC: 12 AN: 26100

East Asian (EAS) AF: 0.00 AC: 0 AN: 39596

South Asian (SAS) AF: 0.00737 AC: 635 AN: 86208

European-Finnish (FIN) AF: 0.00788 AC: 420 AN: 53320

Middle Eastern (MID) AF: 0.00504 AC: 29 AN: 5758

European-Non Finnish (NFE) AF: 0.0101 AC: 11170 AN: 1111270

Other (OTH) AF: 0.00693 AC: 418 AN: 60318

GnomAD4 genome AF: 0.00541 AC: 824 AN: 152280 Hom.: 3 Cov.: 32 AF XY: 0.00522 AC XY: 389 AN XY: 74468

African (AFR) AF: 0.00171 AC: 71 AN: 41550

American (AMR) AF: 0.00209 AC: 32 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5184

South Asian (SAS) AF: 0.00663 AC: 32 AN: 4828

European-Finnish (FIN) AF: 0.00622 AC: 66 AN: 10610

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

European-Non Finnish (NFE) AF: 0.00891 AC: 606 AN: 68028

Other (OTH) AF: 0.00473 AC: 10 AN: 2116

Alfa AF: 0.00620 Hom.: 2

Bravo AF: 0.00500

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.00932

EpiControl AF: 0.00859

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Charcot-Marie-Tooth disease type 4H (2)
-	-	2	not specified (2)
-	-	1	Charcot-Marie-Tooth disease (1)
-	-	1	Charcot-Marie-Tooth disease type 4 (1)
-	-	1	FGD4-related disorder (1)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.29
CADD	Benign	9.2
DANN	Benign	0.73
PhyloP100		-0.064
Mutation Taster		=94/6	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: rs61748364; hg19: chr12-32777927; COSMIC: COSV56782595;