Variant 12-95137593-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_018351.4(FGD6):c.2923A>G(p.Lys975Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00000657 in 152,242 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

FGD6
NM_018351.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.64

Variant links:

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]

FGD6 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FGD6	NM_018351.4 linkuse as main transcript	c.2923A>G	p.Lys975Glu	missense_variant	7/21	ENST00000343958.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FGD6	ENST00000343958.9 linkuse as main transcript	c.2923A>G	p.Lys975Glu	missense_variant	7/21	1	NM_018351.4	P1	Q6ZV73-1
FGD6	ENST00000549499.1 linkuse as main transcript	c.2923A>G	p.Lys975Glu	missense_variant	7/16	1
FGD6	ENST00000451107.3 linkuse as main transcript	c.*318A>G		3_prime_UTR_variant, NMD_transcript_variant	6/20	1
FGD6	ENST00000546711.5 linkuse as main transcript	c.2923A>G	p.Lys975Glu	missense_variant	7/19	5			Q6ZV73-2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152242

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1459100

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

725676

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152242

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74378

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 14, 2023

The c.2923A>G (p.K975E) alteration is located in exon 7 (coding exon 7) of the FGD6 gene. This alteration results from a A to G substitution at nucleotide position 2923, causing the lysine (K) at amino acid position 975 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.51

BayesDel_addAF

Benign

0.0069

BayesDel_noAF

Benign

-0.23

Cadd

Pathogenic

Dann

Uncertain

1.0

DEOGEN2

Benign

0.083

T;.;T

Eigen

Uncertain

0.48

Eigen_PC

Uncertain

0.50

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.95

D;D;D

M_CAP

Benign

0.031

MetaRNN

Uncertain

0.42

T;T;T

MetaSVM

Benign

-0.39

MutationAssessor

Benign

1.4

L;L;.

MutationTaster

Benign

0.86

D;D

PrimateAI

Uncertain

0.75

PROVEAN

Benign

-2.2

N;N;N

REVEL

Benign

0.22

Sift

Benign

0.095

T;T;T

Sift4G

Benign

0.082

T;D;D

Polyphen

1.0

D;P;.

Vest4

0.47

MutPred

0.43

Loss of ubiquitination at K975 (P = 0.027);Loss of ubiquitination at K975 (P = 0.027);Loss of ubiquitination at K975 (P = 0.027);

MVP

0.53

MPC

0.37

ClinPred

0.93

GERP RS

5.1

Varity_R

0.26

gMVP

0.27

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over