rs61753359

Variant names:

• chr12-32640381-G-A
• rs61753359
• NM_001370298.3:c.2560G>A

Your query was ambiguous. Multiple possible variants found:

• chr12-32640381-G-A
• chr12-32640381-G-T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001370298.3(FGD4):​c.2560G>A​(p.Val854Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0015 in 1,614,180 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V854L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (7 hom.)
• Consequence: FGD4 NM_001370298.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8 B:5
• Conservation: PhyloP100: 2.67
• Publications: 13 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.016922116).
• BP6: Variant 12-32640381-G-A is Benign according to our data. Variant chr12-32640381-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 188373.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00125 (191/152288) while in subpopulation NFE AF = 0.00212 (144/68032). AF 95% confidence interval is 0.00183. There are 0 homozygotes in GnomAd4. There are 100 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 7 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.2560G>A	p.Val854Met	missense	Exon 17 of 17	NP_001357227.2	F8VWL3
	FGD4	NM_001384126.1		c.2560G>A	p.Val854Met	missense	Exon 17 of 18	NP_001371055.1
	FGD4	NM_001304481.2		c.2404G>A	p.Val802Met	missense	Exon 17 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.2560G>A	p.Val854Met	missense	Exon 17 of 17	ENSP00000449273.1	F8VWL3
	FGD4	ENST00000531134.7	TSL:2	c.2404G>A	p.Val802Met	missense	Exon 17 of 17	ENSP00000431323.1	B7Z493
	FGD4	ENST00000427716.7	TSL:2	c.2149G>A	p.Val717Met	missense	Exon 18 of 18	ENSP00000394487.2	Q96M96-1

Frequencies

GnomAD3 genomes AF: 0.00126 AC: 192 AN: 152170 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000290

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.000289

Gnomad EAS AF: 0.000771

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.00212

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.00124 AC: 312 AN: 251240 AF XY: 0.00144

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000607

Gnomad ASJ exome AF: 0.000199

Gnomad EAS exome AF: 0.000544

Gnomad FIN exome AF: 0.000554

Gnomad NFE exome AF: 0.00196

Gnomad OTH exome AF: 0.00342

GnomAD4 exome AF: 0.00152 AC: 2229 AN: 1461892 Hom.: 7 Cov.: 31 AF XY: 0.00162 AC XY: 1179 AN XY: 727248

African (AFR) AF: 0.000836 AC: 28 AN: 33480

American (AMR) AF: 0.000715 AC: 32 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000344 AC: 9 AN: 26136

East Asian (EAS) AF: 0.000151 AC: 6 AN: 39700

South Asian (SAS) AF: 0.000893 AC: 77 AN: 86258

European-Finnish (FIN) AF: 0.000861 AC: 46 AN: 53420

Middle Eastern (MID) AF: 0.0201 AC: 116 AN: 5768

European-Non Finnish (NFE) AF: 0.00161 AC: 1795 AN: 1112010

Other (OTH) AF: 0.00199 AC: 120 AN: 60396

GnomAD4 genome AF: 0.00125 AC: 191 AN: 152288 Hom.: 0 Cov.: 32 AF XY: 0.00134 AC XY: 100 AN XY: 74464

African (AFR) AF: 0.000289 AC: 12 AN: 41560

American (AMR) AF: 0.000588 AC: 9 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.000289 AC: 1 AN: 3466

East Asian (EAS) AF: 0.000773 AC: 4 AN: 5176

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4820

European-Finnish (FIN) AF: 0.000377 AC: 4 AN: 10608

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.00212 AC: 144 AN: 68032

Other (OTH) AF: 0.00142 AC: 3 AN: 2116

Alfa AF: 0.00178 Hom.: 4

Bravo AF: 0.00121

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00163 AC: 14

ExAC AF: 0.00131 AC: 159

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00327

EpiControl AF: 0.00279

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	4	2	not provided (6)
-	3	-	Charcot-Marie-Tooth disease type 4H (3)
-	-	1	Charcot-Marie-Tooth disease type 4 (1)
-	-	1	FGD4-related disorder (1)
-	1	-	Inborn genetic diseases (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.43
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.28	T
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.0083	T
MetaRNN	Benign	0.017	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	L
PhyloP100		2.7
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-0.83	N
REVEL	Benign	0.13
Sift	Benign	0.030	D
Sift4G	Uncertain	0.058	T
Polyphen		0.95	P
Vest4		0.32
MVP		0.51
MPC		0.94
ClinPred		0.040	T
GERP RS		4.4
Varity_R		0.11
gMVP		0.25
Mutation Taster		=74/26	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: rs61753359; hg19: chr12-32793315; COSMIC: COSV56783267; COSMIC: COSV56783267;