rs137853267

Variant names:

• chrX-54465797-T-C
• rs137853267
• NM_004463.3:c.1396A>G

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_004463.3(FGD1):​c.1396A>G​(p.Met466Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 21)
• Consequence: FGD1 NM_004463.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 8.02
• Publications: 6 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: Likely_pathogenic. The variant received 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.944
• PP5: Variant X-54465797-T-C is Pathogenic according to our data. Variant chrX-54465797-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 10834.Status of the report is no_assertion_criteria_provided, 0 stars.

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.1396A>G	p.Met466Val	missense	Exon 7 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.1396A>G	p.Met466Val	missense	Exon 7 of 18	ENSP00000364277.3	P98174
	FGD1	ENST00000934021.1		c.1396A>G	p.Met466Val	missense	Exon 7 of 19	ENSP00000604080.1
	FGD1	ENST00000934019.1		c.1396A>G	p.Met466Val	missense	Exon 7 of 18	ENSP00000604078.1

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 21

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Aarskog syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.47	T
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.44	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Uncertain	-0.16	T
MutationAssessor	Benign	1.8	L
PhyloP100		8.0
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-3.8	D
REVEL	Pathogenic	0.70
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.97	D
Vest4		0.73
MutPred		0.86		Gain of methylation at K465 (P = 0.0294)
MVP		0.96
MPC		2.3
ClinPred		0.98	D
GERP RS		5.7
Varity_R		0.95
gMVP		0.92
Mutation Taster		=16/84	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs137853267; hg19: chrX-54492230;