rs12011120

Variant names:

• chrX-54449716-A-G
• rs12011120
• NM_004463.3:c.2091T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_004463.3(FGD1):​c.2091T>C​(p.Thr697Thr) 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:7
• Conservation: PhyloP100: 0.400
• Publications: 7 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 -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 VariationId is 95086.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FGD1	NM_004463.3	MANE Select	c.2091T>C	p.Thr697Thr	synonymous	Exon 14 of 18	NP_004454.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FGD1	ENST00000375135.4	TSL:1 MANE Select	c.2091T>C	p.Thr697Thr	synonymous	Exon 14 of 18	ENSP00000364277.3	P98174
	FGD1	ENST00000934021.1		c.2091T>C	p.Thr697Thr	synonymous	Exon 14 of 19	ENSP00000604080.1
	FGD1	ENST00000934019.1		c.2088T>C	p.Thr696Thr	synonymous	Exon 14 of 18	ENSP00000604078.1

Frequencies

GnomAD3 genomes AF: 0.166 AC: 18294 AN: 110312 Hom.: 3064 Cov.: 22

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

GnomAD2 exomes AF: 0.0743 AC: 13586 AN: 182735 AF XY: 0.0644

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 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

African (AFR) AF: 0.526 AC: 13811 AN: 26266

American (AMR) AF: 0.0443 AC: 1559 AN: 35178

Ashkenazi Jewish (ASJ) AF: 0.0189 AC: 367 AN: 19370

East Asian (EAS) AF: 0.0894 AC: 2698 AN: 30188

South Asian (SAS) AF: 0.0968 AC: 5232 AN: 54065

European-Finnish (FIN) AF: 0.0278 AC: 1126 AN: 40530

Middle Eastern (MID) AF: 0.0646 AC: 266 AN: 4119

European-Non Finnish (NFE) AF: 0.0173 AC: 14504 AN: 840440

Other (OTH) AF: 0.0706 AC: 3249 AN: 46017

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

African (AFR) AF: 0.514 AC: 15473 AN: 30084

American (AMR) AF: 0.0780 AC: 806 AN: 10338

Ashkenazi Jewish (ASJ) AF: 0.0155 AC: 41 AN: 2638

East Asian (EAS) AF: 0.0979 AC: 340 AN: 3472

South Asian (SAS) AF: 0.104 AC: 269 AN: 2577

European-Finnish (FIN) AF: 0.0252 AC: 151 AN: 5987

Middle Eastern (MID) AF: 0.0783 AC: 17 AN: 217

European-Non Finnish (NFE) AF: 0.0192 AC: 1013 AN: 52872

Other (OTH) AF: 0.139 AC: 209 AN: 1501

Alfa AF: 0.0726 Hom.: 4328

Bravo AF: 0.188

EpiCase AF: 0.0229

EpiControl AF: 0.0225

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	7.4
DANN	Benign	0.76
PhyloP100		0.40
Mutation Taster		=100/0	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: rs12011120; hg19: chrX-54476149; COSMIC: COSV64308593; COSMIC: COSV64308593;