rs12011120

chrX-54449716-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_004463.3(FGD1):c.2091T>C(p.Thr697=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0507 in 1,206,541 control chromosomes in the GnomAD database, including 6,368 homozygotes. There are 18,988 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (3067 hom., 5010 hem., cov: 22)
  • Exomes 𝑓: 0.039 (3301 hom. 13978 hem.)
• Consequence: FGD1 NM_004463.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.400

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BP6: Variant X-54449716-A-G is Benign according to our data. Variant chrX-54449716-A-G is described in ClinVar as [Benign]. Clinvar id is 95086.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-54449716-A-G is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.4 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.508 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FGD1	NM_004463.3	c.2091T>C	p.Thr697=	synonymous_variant	14/18	ENST00000375135.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FGD1	ENST00000375135.4	c.2091T>C	p.Thr697=	synonymous_variant	14/18	1	NM_004463.3	P1

Frequencies

GnomAD3 genomes AF: 0.166 AC: 18294 AN: 110312 Hom.: 3064 Cov.: 22 AF XY: 0.153 AC XY: 4989 AN XY: 32564

Gnomad AFR AF: 0.515

Gnomad AMI AF: 0.00587

Gnomad AMR AF: 0.0781

Gnomad ASJ AF: 0.0155

Gnomad EAS AF: 0.0982

Gnomad SAS AF: 0.105

Gnomad FIN AF: 0.0252

Gnomad MID AF: 0.0759

Gnomad NFE AF: 0.0192

Gnomad OTH AF: 0.137

GnomAD3 exomes AF: 0.0743 AC: 13586 AN: 182735 Hom.: 1559 AF XY: 0.0644 AC XY: 4329 AN XY: 67229

Gnomad AFR exome AF: 0.529

Gnomad AMR exome AF: 0.0398

Gnomad ASJ exome AF: 0.0157

Gnomad EAS exome AF: 0.0964

Gnomad SAS exome AF: 0.0999

Gnomad FIN exome AF: 0.0288

Gnomad NFE exome AF: 0.0187

Gnomad OTH exome AF: 0.0485

GnomAD4 exome AF: 0.0391 AC: 42812 AN: 1096173 Hom.: 3301 Cov.: 29 AF XY: 0.0386 AC XY: 13978 AN XY: 361799

Gnomad4 AFR exome AF: 0.526

Gnomad4 AMR exome AF: 0.0443

Gnomad4 ASJ exome AF: 0.0189

Gnomad4 EAS exome AF: 0.0894

Gnomad4 SAS exome AF: 0.0968

Gnomad4 FIN exome AF: 0.0278

Gnomad4 NFE exome AF: 0.0173

Gnomad4 OTH exome AF: 0.0706

GnomAD4 genome AF: 0.166 AC: 18323 AN: 110368 Hom.: 3067 Cov.: 22 AF XY: 0.154 AC XY: 5010 AN XY: 32630

Gnomad4 AFR AF: 0.514

Gnomad4 AMR AF: 0.0780

Gnomad4 ASJ AF: 0.0155

Gnomad4 EAS AF: 0.0979

Gnomad4 SAS AF: 0.104

Gnomad4 FIN AF: 0.0252

Gnomad4 NFE AF: 0.0192

Gnomad4 OTH AF: 0.139

Alfa AF: 0.0507 Hom.: 2220

Bravo AF: 0.188

EpiCase AF: 0.0229

EpiControl AF: 0.0225

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	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 28, 2018	p.Thr697Thr in exon 14 of FGD1: This variant is not expected to have clinical significance because it does not alter an amino acid residue, is not located within the splice consensus sequence, and has been identified in 52.77% (4481/8491) of African chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs12011120). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 16, 2012	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2021	- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 12, 2015

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	-0.63
Cadd	Benign	7.4
Dann	Benign	0.76

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: rs12011120; hg19: chrX-54476149; COSMIC: COSV64308593; COSMIC: COSV64308593;