chrX-54470441-C-T

Position:

chrX-54470441-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBS1BS2

The NM_004463.3(FGD1):c.676G>A(p.Ala226Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00321 in 1,203,728 control chromosomes in the GnomAD database, including 8 homozygotes. There are 1,169 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0025 ( 0 hom., 99 hem., cov: 23)

Exomes 𝑓: 0.0033 ( 8 hom. 1070 hem. )

Consequence

FGD1
NM_004463.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -0.0210

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), FGD1. . Gene score misZ 3.5183 (greater than the threshold 3.09). GenCC has associacion of gene with Aarskog-Scott syndrome, X-linked.

BP4

Computational evidence support a benign effect (MetaRNN=0.004192412).

BP6

Variant X-54470441-C-T is Benign according to our data. Variant chrX-54470441-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 95094.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-54470441-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00252 (281/111549) while in subpopulation AMR AF= 0.00653 (69/10573). AF 95% confidence interval is 0.00529. There are 0 homozygotes in gnomad4. There are 99 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.

BS2

High Hemizygotes in GnomAd4 at 99 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FGD1	NM_004463.3 linkuse as main transcript	c.676G>A	p.Ala226Thr	missense_variant	4/18	ENST00000375135.4	NP_004454.2	P98174A0A024R9Y5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FGD1	ENST00000375135.4 linkuse as main transcript	c.676G>A	p.Ala226Thr	missense_variant	4/18	1	NM_004463.3	ENSP00000364277.3		P98174

Frequencies

GnomAD3 genomes

AF:

0.00252

AC:

281

AN:

111497

Hom.:

Cov.:

AF XY:

0.00294

AC XY:

AN XY:

33713

show subpopulations

Gnomad AFR

AF:

0.000457

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00653

Gnomad ASJ

AF:

0.000378

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000375

Gnomad FIN

AF:

0.00362

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00323

Gnomad OTH

AF:

0.00201

GnomAD3 exomes

AF:

0.00268

AC:

463

AN:

172713

Hom.:

AF XY:

0.00212

AC XY:

128

AN XY:

60305

show subpopulations

Gnomad AFR exome

AF:

0.000250

Gnomad AMR exome

AF:

0.00288

Gnomad ASJ exome

AF:

0.000814

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000221

Gnomad FIN exome

AF:

0.00460

Gnomad NFE exome

AF:

0.00383

Gnomad OTH exome

AF:

0.00371

GnomAD4 exome

AF:

0.00328

AC:

3581

AN:

1092179

Hom.:

Cov.:

AF XY:

0.00297

AC XY:

1070

AN XY:

359709

show subpopulations

Gnomad4 AFR exome

AF:

0.000304

Gnomad4 AMR exome

AF:

0.00265

Gnomad4 ASJ exome

AF:

0.00103

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000932

Gnomad4 FIN exome

AF:

0.00441

Gnomad4 NFE exome

AF:

0.00375

Gnomad4 OTH exome

AF:

0.00300

GnomAD4 genome

AF:

0.00252

AC:

281

AN:

111549

Hom.:

Cov.:

AF XY:

0.00293

AC XY:

AN XY:

33775

show subpopulations

Gnomad4 AFR

AF:

0.000456

Gnomad4 AMR

AF:

0.00653

Gnomad4 ASJ

AF:

0.000378

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000376

Gnomad4 FIN

AF:

0.00362

Gnomad4 NFE

AF:

0.00323

Gnomad4 OTH

AF:

0.00199

Alfa

AF:

0.00317

Hom.:

130

Bravo

AF:

0.00252

TwinsUK

AF:

0.00216

AC:

ALSPAC

AF:

0.00381

AC:

ESP6500AA

AF:

0.000523

AC:

ESP6500EA

AF:

0.00343

AC:

ExAC

AF:

0.00231

AC:

280

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:6

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 24, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jun 01, 2017	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Feb 11, 2014

- -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 27, 2017

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

FGD1-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 28, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.080

BayesDel_addAF

Benign

-0.77

BayesDel_noAF

Benign

-0.88

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.066

FATHMM_MKL

Benign

0.029

LIST_S2

Benign

0.65

M_CAP

Benign

0.013

MetaRNN

Benign

0.0042

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

PrimateAI

Uncertain

0.59

PROVEAN

Benign

-0.49

REVEL

Benign

0.036

Sift

Benign

0.19

Sift4G

Benign

0.78

Polyphen

0.012

Vest4

0.017

MVP

0.28

MPC

0.30

ClinPred

0.011

GERP RS

1.5

Varity_R

0.048

gMVP

0.12

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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