rs137853267

Positions:

• chrX-54465797-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PP2 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

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 Likely_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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.
• 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 id is 10834.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chrX-54465797-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FGD1	NM_004463.3	c.1396A>G	p.Met466Val	missense_variant	7/18	ENST00000375135.4	NP_004454.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FGD1	ENST00000375135.4	c.1396A>G	p.Met466Val	missense_variant	7/18	1	NM_004463.3	ENSP00000364277.3

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 21

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Aarskog syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 01, 2007

- -

Computational scores

Source: dbNSFP v4.3

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
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

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

Publications

LitVar

Other links and lift over

dbSNP: rs137853267; hg19: chrX-54492230;