rs779475596

chrX-54495371-T-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 1P and 11B. PP2 BP4_Moderate BP6 BS1 BS2

The NM_004463.3(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 NM_004463.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: -0.110

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]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• PP2: Missense variant where missense usually causes diseases, FGD1
• 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 GnomAdExome at 3 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FGD1	NM_004463.3	c.62A>T	p.Asn21Ile	missense_variant	1/18	ENST00000375135.4

Ensembl

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

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD3 exomes AF: 0.000170 AC: 14 AN: 82351 Hom.: 0 AF XY: 0.000118 AC XY: 3 AN XY: 25465

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: 15 AN: 1030797 Hom.: 0 Cov.: 31 AF XY: 0.00000904 AC XY: 3 AN XY: 331811

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.: 22

Bravo AF: 0.0000302

ExAC AF: 0.0000762 AC: 4

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

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

Invitae

Oct 24, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.57
Cadd	Benign	15
Dann	Uncertain	0.98
DEOGEN2	Benign	0.087	T
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.59	T
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.077	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N
MutationTaster	Benign	1.0	N
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-0.81	N
REVEL	Benign	0.044
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.034	D
Polyphen		0.35	B
Vest4		0.17
MutPred		0.24		Gain of catalytic residue at P23 (P = 0.0535);
MVP		0.36
MPC		0.84
ClinPred		0.11	T
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

Other links and lift over

dbSNP: rs779475596; hg19: chrX-54521804;