12-32534409-T-C

Position:

• chr12-32534409-T-C

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_Moderate BS1_Supporting BS2

The NM_001370298.3(FGD4):​c.167-29728T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00108 in 1,507,940 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00058 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0011 (3 hom.)
• Consequence: FGD4 NM_001370298.3 intron
• Clinical Significance: Uncertain significance criteria provided, single submitter U:3
• Conservation: PhyloP100: 0.841

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]

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.13948706).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000585 (89/152260) while in subpopulation NFE AF= 0.00116 (79/68044). AF 95% confidence interval is 0.000954. There are 0 homozygotes in gnomad4. There are 39 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FGD4	NM_001370298.3	c.167-29728T>C		intron_variant		ENST00000534526.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FGD4	ENST00000534526.7	c.167-29728T>C		intron_variant		5	NM_001370298.3

Frequencies

GnomAD3 genomes AF: 0.000585 AC: 89 AN: 152260 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00116

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000585 AC: 67 AN: 114606 Hom.: 0 AF XY: 0.000570 AC XY: 36 AN XY: 63130

Gnomad AFR exome AF: 0.000168

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00141

Gnomad OTH exome AF: 0.000285

GnomAD4 exome AF: 0.00114 AC: 1542 AN: 1355680 Hom.: 3 Cov.: 29 AF XY: 0.00114 AC XY: 762 AN XY: 668822

Gnomad4 AFR exome AF: 0.000231

Gnomad4 AMR exome AF: 0.0000669

Gnomad4 ASJ exome AF: 0.0000424

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00141

Gnomad4 OTH exome AF: 0.000496

GnomAD4 genome AF: 0.000585 AC: 89 AN: 152260 Hom.: 0 Cov.: 33 AF XY: 0.000524 AC XY: 39 AN XY: 74380

Gnomad4 AFR AF: 0.000217

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00116

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000502 Hom.: 0

Bravo AF: 0.000574

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.000778 AC: 3

ExAC AF: 0.000132 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:3

Uncertain significance, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	16
DANN	Benign	0.82
DEOGEN2	Benign	0.0080	T
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.40
FATHMM_MKL	Benign	0.15	N
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.35	D
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-0.74	T
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PROVEAN	Benign	0.32	N
REVEL	Benign	0.088
Sift	Pathogenic	0.0	D
Polyphen		0.067	B
Vest4		0.54
MVP		0.81
ClinPred		0.11	T
GERP RS		3.9
gMVP		0.14

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

Publications

LitVar

Other links and lift over

dbSNP: rs561223009; hg19: chr12-32687343;