Genetic Variant FGD1:p.Arg935Gly (chrX-54446192-T-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_004463.3(FGD1):c.2803A>G(p.Arg935Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000888 in 112,580 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. R935R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000089 ( 0 hom., 1 hem., cov: 23)

Consequence

FGD1
NM_004463.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.21

Publications

0 publications found

Variant links:

Genes affected

FGD1 (HGNC:3663): (FYVE, RhoGEF and PH domain containing 1) This gene encodes a protein that contains Dbl (DH) and pleckstrin (PH) homology domains and is similar to the Rho family of small GTP-binding proteins. The encoded protein specifically binds to the Rho family GTPase Cdc42Hs and can stimulate the GDP-GTP exchange of the isoprenylated form of Cdc42Hs. It also stimulates the mitogen activated protein kinase cascade leading to c-Jun kinase SAPK/JNK1 activation. Defects in this gene are the cause of the faciogenital dysplasia in Aarskog-Scott syndrome and a syndromatic form of X-linked cognitive disability. [provided by RefSeq, Jul 2017]

FGD1 links:

TSR2 (HGNC:25455): (TSR2 ribosome maturation factor) The protein encoded by this gene appears to repress the transcription of NF-kappaB and may be involved in apoptosis. Defects in this gene are a cause of Diamond-Blackfan anemia. [provided by RefSeq, Oct 2016]

TSR2 Gene-Disease associations (from GenCC):

Diamond-Blackfan anemia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Diamond-Blackfan anemia 14 with mandibulofacial dysostosis
Inheritance: XL Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

TSR2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.06918621).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004463.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FGD1	NM_004463.3	MANE Select	c.2803A>G	p.Arg935Gly	missense	Exon 18 of 18	NP_004454.2
TSR2	NM_058163.3	MANE Select	c.*1642T>C		3_prime_UTR	Exon 5 of 5	NP_477511.1	Q969E8
TSR2	NM_001346789.2		c.*1642T>C		3_prime_UTR	Exon 5 of 5	NP_001333718.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FGD1	ENST00000375135.4	TSL:1 MANE Select	c.2803A>G	p.Arg935Gly	missense	Exon 18 of 18	ENSP00000364277.3	P98174
TSR2	ENST00000375151.5	TSL:1 MANE Select	c.*1642T>C		3_prime_UTR	Exon 5 of 5	ENSP00000364293.4	Q969E8
FGD1	ENST00000934021.1		c.2803A>G	p.Arg935Gly	missense	Exon 19 of 19	ENSP00000604080.1

Frequencies

GnomAD3 genomes

AF:

0.00000888

AC:

AN:

112580

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000323

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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

Cov.:

GnomAD4 genome

AF:

0.00000888

AC:

AN:

112580

Hom.:

Cov.:

AF XY:

0.0000288

AC XY:

AN XY:

34726

show subpopulations

African (AFR)

AF:

0.0000323

AC:

AN:

30965

American (AMR)

AF:

0.00

AC:

AN:

10707

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2648

East Asian (EAS)

AF:

0.00

AC:

AN:

3551

South Asian (SAS)

AF:

0.00

AC:

AN:

2756

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6242

Middle Eastern (MID)

AF:

0.00

AC:

AN:

238

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53258

Other (OTH)

AF:

0.00

AC:

AN:

1529

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Aarskog syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.078

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.71

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.066

FATHMM_MKL

Benign

0.40

LIST_S2

Benign

0.76

M_CAP

Benign

0.019

MetaRNN

Benign

0.069

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.55

PhyloP100

1.2

PrimateAI

Benign

0.45

PROVEAN

Benign

-0.95

REVEL

Benign

0.11

Sift

Benign

0.094

Sift4G

Benign

0.35

Polyphen

0.0

Vest4

0.15

MutPred

0.14

Gain of glycosylation at S932 (P = 0.0502)

MVP

0.45

MPC

1.5

ClinPred

0.12

GERP RS

3.5

Varity_R

0.17

gMVP

0.28

Mutation Taster

=96/4

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over