rs779475596

Positions:

chrX-54495371-T-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 1P and 11B. PP2BP4_ModerateBP6BS1BS2

The ENST00000375135.4(FGD1):c.62A>T(p.Asn21Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000146 in 1,030,797 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: not found (cov: 22)

Exomes 𝑓: 0.000015 ( 0 hom. 3 hem. )

Consequence

FGD1
ENST00000375135.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: -0.110

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 -10 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=0.07740399).

BP6

Variant X-54495371-T-A is Benign according to our data. Variant chrX-54495371-T-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 447320.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=2}.

BS1

Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.0000146 (15/1030797) while in subpopulation AMR AF= 0.000569 (15/26350). AF 95% confidence interval is 0.000351. There are 0 homozygotes in gnomad4_exome. There are 3 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Hemizygotes in GnomAdExome4 at 3 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FGD1	NM_004463.3 linkuse as main transcript	c.62A>T	p.Asn21Ile	missense_variant	1/18	ENST00000375135.4	NP_004454.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FGD1	ENST00000375135.4 linkuse as main transcript	c.62A>T	p.Asn21Ile	missense_variant	1/18	1	NM_004463.3	ENSP00000364277	P1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.000170

AC:

AN:

82351

Hom.:

AF XY:

0.000118

AC XY:

AN XY:

25465

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000812

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000146

AC:

AN:

1030797

Hom.:

Cov.:

AF XY:

0.00000904

AC XY:

AN XY:

331811

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000569

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

Cov.:

Bravo

AF:

0.0000302

ExAC

AF:

0.0000762

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Athena Diagnostics

May 04, 2017

- -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 26, 2018

The p.N21I variant (also known as c.62A>T), located in coding exon 1 of the FGD1 gene, results from an A to T substitution at nucleotide position 62. The asparagine at codon 21 is replaced by isoleucine, an amino acid with dissimilar properties. Based on data from gnomAD, the T allele has an overall frequency of approximately 0.018% (14/78876) total alleles studied. The highest observed frequency was 0.083% (14/16757) of Latino alleles, including 3 hemizygotes. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 24, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.099

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.57

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.087

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.59

M_CAP

Uncertain

0.16

MetaRNN

Benign

0.077

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.55

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.83

PROVEAN

Benign

-0.81

REVEL

Benign

0.044

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.034

Polyphen

0.35

Vest4

0.17

MutPred

0.24

Gain of catalytic residue at P23 (P = 0.0535);

MVP

0.36

MPC

0.84

ClinPred

0.11

GERP RS

1.6

Varity_R

0.17

gMVP

0.18

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

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