rs375389604

Variant names:

• chrX-54455787-A-G
• rs375389604
• NM_004463.3:c.1843-3T>C

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_004463.3(FGD1):​c.1843-3T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000282 in 1,172,219 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 7 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., 6 hem., cov: 24)
  • Exomes 𝑓: 0.000012 (0 hom. 1 hem.)
• Consequence: FGD1 NM_004463.3 splice_region, intron
• Scores: Splicing: ADA: 0.002426
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.98
• 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.39).
• BS2: High AC in GnomAd4 at 20 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FGD1	NM_004463.3	MANE Select	c.1843-3T>C		splice_region intron	N/A	NP_004454.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FGD1	ENST00000375135.4	TSL:1 MANE Select	c.1843-3T>C		splice_region intron	N/A	ENSP00000364277.3

Frequencies

GnomAD3 genomes AF: 0.000177 AC: 20 AN: 113210 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.000640

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000319 AC: 4 AN: 125486 AF XY: 0.00

Gnomad AFR exome AF: 0.000475

Gnomad AMR exome AF: 0.00

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: 0.0000123 AC: 13 AN: 1058954 Hom.: 0 Cov.: 30 AF XY: 0.00000292 AC XY: 1 AN XY: 342392

African (AFR) AF: 0.000353 AC: 9 AN: 25460

American (AMR) AF: 0.00 AC: 0 AN: 29467

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18736

East Asian (EAS) AF: 0.00 AC: 0 AN: 28218

South Asian (SAS) AF: 0.00 AC: 0 AN: 50312

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38208

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4093

European-Non Finnish (NFE) AF: 0.00000244 AC: 2 AN: 819849

Other (OTH) AF: 0.0000448 AC: 2 AN: 44611

GnomAD4 genome AF: 0.000177 AC: 20 AN: 113265 Hom.: 0 Cov.: 24 AF XY: 0.000169 AC XY: 6 AN XY: 35399

African (AFR) AF: 0.000638 AC: 20 AN: 31325

American (AMR) AF: 0.00 AC: 0 AN: 10735

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2655

East Asian (EAS) AF: 0.00 AC: 0 AN: 3578

South Asian (SAS) AF: 0.00 AC: 0 AN: 2789

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6307

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 219

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53422

Other (OTH) AF: 0.00 AC: 0 AN: 1551

Alfa AF: 0.000214 Hom.: 1

Bravo AF: 0.000151

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.39
CADD	Benign	15
DANN	Benign	0.84
PhyloP100		2.0
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0024
dbscSNV1_RF	Benign	0.016
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: rs375389604; hg19: chrX-54482220;