rs779475596

Variant names:

• chrX-54495371-T-A
• rs779475596
• NM_004463.3:c.62A>T

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BP6 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. 13/21 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
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• Aarskog-Scott syndrome, X-linked

  Inheritance: AD, XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P, ClinGen

ACMG classification

Our verdict: Benign. The variant received -7 ACMG points.

• 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 VariationId is 447320.
• BS2: High AC in GnomAdExome4 at 15 AD,XL gene.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FGD1	NM_004463.3	MANE Select	c.62A>T	p.Asn21Ile	missense	Exon 1 of 18	NP_004454.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FGD1	ENST00000375135.4	TSL:1 MANE Select	c.62A>T	p.Asn21Ile	missense	Exon 1 of 18	ENSP00000364277.3	P98174
	FGD1	ENST00000934021.1		c.62A>T	p.Asn21Ile	missense	Exon 1 of 19	ENSP00000604080.1
	FGD1	ENST00000934019.1		c.62A>T	p.Asn21Ile	missense	Exon 1 of 18	ENSP00000604078.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD2 exomes AF: 0.000170 AC: 14 AN: 82351 AF XY: 0.000118

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 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

African (AFR) AF: 0.00 AC: 0 AN: 24103

American (AMR) AF: 0.000569 AC: 15 AN: 26350

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17858

East Asian (EAS) AF: 0.00 AC: 0 AN: 26759

South Asian (SAS) AF: 0.00 AC: 0 AN: 47727

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 28649

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2818

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 813037

Other (OTH) AF: 0.00 AC: 0 AN: 43496

GnomAD4 genome Cov.: 22

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000302

ExAC AF: 0.0000762 AC: 4

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)
-	-	1	not provided (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		-0.11
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
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs779475596; hg19: chrX-54521804;