rs147035080

Positions:

• chrX-54495436-C-G

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.-4G>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0813 in 1,004,033 control chromosomes in the GnomAD database, including 2,344 homozygotes. There are 25,995 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.050 (172 hom., 1550 hem., cov: 22)
  • Exomes 𝑓: 0.085 (2172 hom. 24445 hem.)
• Consequence: FGD1 NM_004463.3 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.0900

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=-0.53).
• BP6: Variant X-54495436-C-G is Benign according to our data. Variant chrX-54495436-C-G is described in ClinVar as [Benign]. Clinvar id is 95077.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-54495436-C-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0749 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FGD1	NM_004463.3	c.-4G>C		5_prime_UTR_variant	1/18	ENST00000375135.4	NP_004454.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FGD1	ENST00000375135.4	c.-4G>C		5_prime_UTR_variant	1/18	1	NM_004463.3	ENSP00000364277	P1

Frequencies

GnomAD3 genomes AF: 0.0504 AC: 5563 AN: 110276 Hom.: 173 Cov.: 22 AF XY: 0.0473 AC XY: 1556 AN XY: 32870

Gnomad AFR AF: 0.0114

Gnomad AMI AF: 0.0835

Gnomad AMR AF: 0.0229

Gnomad ASJ AF: 0.0675

Gnomad EAS AF: 0.000583

Gnomad SAS AF: 0.0769

Gnomad FIN AF: 0.0778

Gnomad MID AF: 0.0307

Gnomad NFE AF: 0.0769

Gnomad OTH AF: 0.0413

GnomAD3 exomes AF: 0.254 AC: 1525 AN: 5995 Hom.: 43 AF XY: 0.534 AC XY: 383 AN XY: 717

Gnomad AFR exome AF: 0.247

Gnomad AMR exome AF: 0.137

Gnomad ASJ exome AF: 0.435

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.386

Gnomad FIN exome AF: 0.184

Gnomad NFE exome AF: 0.302

Gnomad OTH exome AF: 0.261

GnomAD4 exome AF: 0.0851 AC: 76073 AN: 893715 Hom.: 2172 Cov.: 29 AF XY: 0.0896 AC XY: 24445 AN XY: 272959

Gnomad4 AFR exome AF: 0.0101

Gnomad4 AMR exome AF: 0.0352

Gnomad4 ASJ exome AF: 0.0818

Gnomad4 EAS exome AF: 0.000192

Gnomad4 SAS exome AF: 0.138

Gnomad4 FIN exome AF: 0.0967

Gnomad4 NFE exome AF: 0.0883

Gnomad4 OTH exome AF: 0.0715

GnomAD4 genome AF: 0.0503 AC: 5553 AN: 110318 Hom.: 172 Cov.: 22 AF XY: 0.0471 AC XY: 1550 AN XY: 32922

Gnomad4 AFR AF: 0.0113

Gnomad4 AMR AF: 0.0228

Gnomad4 ASJ AF: 0.0675

Gnomad4 EAS AF: 0.000585

Gnomad4 SAS AF: 0.0749

Gnomad4 FIN AF: 0.0778

Gnomad4 NFE AF: 0.0769

Gnomad4 OTH AF: 0.0401

Alfa AF: 0.0629 Hom.: 448

Bravo AF: 0.0449

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 17, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 14, 2019	c.-4G>C in the 5'UTR of FGD1: This variant is is not expected to have clinical significance because it has been identified in 9.8% (2533/25820) of total chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs147035080). ACMG/AMP Criteria applied: BA1 -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2021	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 24, 2014

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	16
DANN	Benign	0.91
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs147035080; hg19: chrX-54521869; COSMIC: COSV64309332;