rs147035080

Variant names:

• chrX-54495436-C-G
• rs147035080
• NM_004463.3:c.-4G>C

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 3 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: Benign. The variant received -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 VariationId is 95077.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
FGD1	NM_004463.3	c.-4G>C		5_prime_UTR_variant	Exon 1 of 18	ENST00000375135.4	NP_004454.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FGD1	ENST00000375135.4	c.-4G>C		5_prime_UTR_variant	Exon 1 of 18	1	NM_004463.3	ENSP00000364277.3

Frequencies

GnomAD3 genomes AF: 0.0504 AC: 5563 AN: 110276 Hom.: 173 Cov.: 22

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

GnomAD2 exomes AF: 0.254 AC: 1525 AN: 5995 AF XY: 0.534

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 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

African (AFR) AF: 0.0101 AC: 182 AN: 18083

American (AMR) AF: 0.0352 AC: 266 AN: 7558

Ashkenazi Jewish (ASJ) AF: 0.0818 AC: 960 AN: 11729

East Asian (EAS) AF: 0.000192 AC: 4 AN: 20822

South Asian (SAS) AF: 0.138 AC: 3692 AN: 26710

European-Finnish (FIN) AF: 0.0967 AC: 2062 AN: 21333

Middle Eastern (MID) AF: 0.0726 AC: 164 AN: 2260

European-Non Finnish (NFE) AF: 0.0883 AC: 66090 AN: 748106

Other (OTH) AF: 0.0715 AC: 2653 AN: 37114

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

African (AFR) AF: 0.0113 AC: 347 AN: 30585

American (AMR) AF: 0.0228 AC: 243 AN: 10653

Ashkenazi Jewish (ASJ) AF: 0.0675 AC: 177 AN: 2622

East Asian (EAS) AF: 0.000585 AC: 2 AN: 3420

South Asian (SAS) AF: 0.0749 AC: 197 AN: 2630

European-Finnish (FIN) AF: 0.0778 AC: 451 AN: 5797

Middle Eastern (MID) AF: 0.0290 AC: 6 AN: 207

European-Non Finnish (NFE) AF: 0.0769 AC: 4015 AN: 52237

Other (OTH) AF: 0.0401 AC: 61 AN: 1520

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

Apr 17, 2018

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 14, 2019

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

May 04, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Inborn genetic diseases Benign:1

Nov 24, 2014

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
PhyloP100		-0.090
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=300/0	polymorphism (auto)

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

Other links and lift over

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