rs10507047

chr12-95210514-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_018351.4(FGD6):c.770A>G(p.Gln257Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.106 in 1,613,868 control chromosomes in the GnomAD database, including 10,259 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.11 (989 hom., cov: 32)
  • Exomes 𝑓: 0.11 (9270 hom.)
• Consequence: FGD6 NM_018351.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.63

Genes affected

FGD6 (HGNC:21740): (FYVE, RhoGEF and PH domain containing 6) Predicted to enable guanyl-nucleotide exchange factor activity and small GTPase binding activity. Predicted to be involved in several processes, including filopodium assembly; regulation of GTPase activity; and regulation of cell shape. Predicted to be located in Golgi apparatus; lamellipodium; and ruffle. Predicted to be active in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0033772886).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.239 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FGD6	NM_018351.4	c.770A>G	p.Gln257Arg	missense_variant	2/21	ENST00000343958.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FGD6	ENST00000343958.9	c.770A>G	p.Gln257Arg	missense_variant	2/21	1	NM_018351.4	P1
FGD6	ENST00000549499.1	c.770A>G	p.Gln257Arg	missense_variant	2/16	1
FGD6	ENST00000451107.3	c.16+6711A>G		intron_variant, NMD_transcript_variant		1
FGD6	ENST00000546711.5	c.770A>G	p.Gln257Arg	missense_variant	2/19	5

Frequencies

GnomAD3 genomes AF: 0.109 AC: 16614 AN: 152138 Hom.: 982 Cov.: 32

Gnomad AFR AF: 0.0982

Gnomad AMI AF: 0.300

Gnomad AMR AF: 0.145

Gnomad ASJ AF: 0.0844

Gnomad EAS AF: 0.250

Gnomad SAS AF: 0.100

Gnomad FIN AF: 0.0912

Gnomad MID AF: 0.0892

Gnomad NFE AF: 0.0990

Gnomad OTH AF: 0.126

GnomAD3 exomes AF: 0.120 AC: 30208 AN: 250828 Hom.: 2151 AF XY: 0.116 AC XY: 15775 AN XY: 135574

Gnomad AFR exome AF: 0.101

Gnomad AMR exome AF: 0.191

Gnomad ASJ exome AF: 0.0808

Gnomad EAS exome AF: 0.225

Gnomad SAS exome AF: 0.0977

Gnomad FIN exome AF: 0.0918

Gnomad NFE exome AF: 0.100

Gnomad OTH exome AF: 0.111

GnomAD4 exome AF: 0.106 AC: 154750 AN: 1461612 Hom.: 9270 Cov.: 35 AF XY: 0.106 AC XY: 76722 AN XY: 727120

Gnomad4 AFR exome AF: 0.0955

Gnomad4 AMR exome AF: 0.186

Gnomad4 ASJ exome AF: 0.0771

Gnomad4 EAS exome AF: 0.283

Gnomad4 SAS exome AF: 0.0984

Gnomad4 FIN exome AF: 0.0916

Gnomad4 NFE exome AF: 0.0984

Gnomad4 OTH exome AF: 0.111

GnomAD4 genome AF: 0.109 AC: 16643 AN: 152256 Hom.: 989 Cov.: 32 AF XY: 0.110 AC XY: 8159 AN XY: 74438

Gnomad4 AFR AF: 0.0983

Gnomad4 AMR AF: 0.145

Gnomad4 ASJ AF: 0.0844

Gnomad4 EAS AF: 0.251

Gnomad4 SAS AF: 0.0993

Gnomad4 FIN AF: 0.0912

Gnomad4 NFE AF: 0.0990

Gnomad4 OTH AF: 0.129

Alfa AF: 0.104 Hom.: 2343

Bravo AF: 0.116

TwinsUK AF: 0.0965 AC: 358

ALSPAC AF: 0.0913 AC: 352

ESP6500AA AF: 0.0958 AC: 422

ESP6500EA AF: 0.0972 AC: 836

ExAC AF: 0.117 AC: 14217

Asia WGS AF: 0.215 AC: 745 AN: 3478

EpiCase AF: 0.107

EpiControl AF: 0.101

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.37
Cadd	Benign	8.2
Dann	Benign	0.97
DEOGEN2	Benign	0.019	T;.;T
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.34
FATHMM_MKL	Benign	0.43	N
LIST_S2	Benign	0.38	T;T;T
MetaRNN	Benign	0.0034	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	M;M;.
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-1.2	N;N;N
REVEL	Benign	0.14
Sift	Uncertain	0.029	D;D;T
Sift4G	Benign	0.078	T;T;T
Polyphen		0.48	P;.;.
Vest4		0.042
MPC		0.13
ClinPred		0.014	T
GERP RS		4.8
Varity_R		0.090
gMVP		0.11

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: rs10507047; hg19: chr12-95604290; COSMIC: COSV59690373; COSMIC: COSV59690373;