rs3830137

chrX-54455400-C-GchrX-54455400-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004463.3(FGD1):c.2015+48G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.205 in 1,023,584 control chromosomes in the GnomAD database, including 27,486 homozygotes. There are 61,737 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.37 (9193 hom., 11931 hem., cov: 23)
  • Exomes 𝑓: 0.19 (18293 hom. 49806 hem.)
• Consequence: FGD1 NM_004463.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.141

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BP6: Variant X-54455400-C-G is Benign according to our data. Variant chrX-54455400-C-G is described in ClinVar as [Benign]. Clinvar id is 259403.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.831 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FGD1	NM_004463.3	c.2015+48G>C		intron_variant		ENST00000375135.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FGD1	ENST00000375135.4	c.2015+48G>C		intron_variant		1	NM_004463.3	P1

Frequencies

GnomAD3 genomes AF: 0.366 AC: 40741 AN: 111400 Hom.: 9188 Cov.: 23 AF XY: 0.354 AC XY: 11885 AN XY: 33588

Gnomad AFR AF: 0.840

Gnomad AMI AF: 0.0472

Gnomad AMR AF: 0.354

Gnomad ASJ AF: 0.104

Gnomad EAS AF: 0.582

Gnomad SAS AF: 0.272

Gnomad FIN AF: 0.122

Gnomad MID AF: 0.199

Gnomad NFE AF: 0.133

Gnomad OTH AF: 0.342

GnomAD3 exomes AF: 0.269 AC: 43883 AN: 163058 Hom.: 7195 AF XY: 0.242 AC XY: 12522 AN XY: 51698

Gnomad AFR exome AF: 0.853

Gnomad AMR exome AF: 0.363

Gnomad ASJ exome AF: 0.115

Gnomad EAS exome AF: 0.579

Gnomad SAS exome AF: 0.260

Gnomad FIN exome AF: 0.131

Gnomad NFE exome AF: 0.131

Gnomad OTH exome AF: 0.208

GnomAD4 exome AF: 0.185 AC: 168877 AN: 912129 Hom.: 18293 Cov.: 16 AF XY: 0.192 AC XY: 49806 AN XY: 259181

Gnomad4 AFR exome AF: 0.854

Gnomad4 AMR exome AF: 0.366

Gnomad4 ASJ exome AF: 0.116

Gnomad4 EAS exome AF: 0.600

Gnomad4 SAS exome AF: 0.260

Gnomad4 FIN exome AF: 0.133

Gnomad4 NFE exome AF: 0.132

Gnomad4 OTH exome AF: 0.235

GnomAD4 genome AF: 0.366 AC: 40792 AN: 111455 Hom.: 9193 Cov.: 23 AF XY: 0.355 AC XY: 11931 AN XY: 33651

Gnomad4 AFR AF: 0.840

Gnomad4 AMR AF: 0.353

Gnomad4 ASJ AF: 0.104

Gnomad4 EAS AF: 0.582

Gnomad4 SAS AF: 0.270

Gnomad4 FIN AF: 0.122

Gnomad4 NFE AF: 0.133

Gnomad4 OTH AF: 0.341

Alfa AF: 0.226 Hom.: 2309

Bravo AF: 0.408

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 11, 2021

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
Cadd	Benign	3.8
Dann	Benign	0.48

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: rs3830137; hg19: chrX-54481833; COSMIC: COSV104426814;