chrX-54449671-T-C

Variant names:

• chrX-54449671-T-C
• rs1126744
• NM_004463.3:c.2136A>G

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.2136A>G​(p.Pro712Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0454 in 1,190,574 control chromosomes in the GnomAD database, including 4,535 homozygotes. There are 16,461 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P712P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.14 (2127 hom., 4185 hem., cov: 21)
  • Exomes 𝑓: 0.036 (2408 hom. 12276 hem.)
• Consequence: FGD1 NM_004463.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.872
• 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=-0.96).
• BP6: Variant X-54449671-T-C is Benign according to our data. Variant chrX-54449671-T-C is described in ClinVar as Benign. ClinVar VariationId is 95089.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.872 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.418 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.2136A>G	p.Pro712Pro	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.2136A>G	p.Pro712Pro	synonymous	Exon 14 of 18	ENSP00000364277.3	P98174
	FGD1	ENST00000934021.1		c.2136A>G	p.Pro712Pro	synonymous	Exon 14 of 19	ENSP00000604080.1
	FGD1	ENST00000934019.1		c.2133A>G	p.Pro711Pro	synonymous	Exon 14 of 18	ENSP00000604078.1

Frequencies

GnomAD3 genomes AF: 0.140 AC: 15410 AN: 109762 Hom.: 2125 Cov.: 21

Gnomad AFR AF: 0.425

Gnomad AMI AF: 0.00590

Gnomad AMR AF: 0.0711

Gnomad ASJ AF: 0.0156

Gnomad EAS AF: 0.0977

Gnomad SAS AF: 0.105

Gnomad FIN AF: 0.0254

Gnomad MID AF: 0.0812

Gnomad NFE AF: 0.0191

Gnomad OTH AF: 0.125

GnomAD2 exomes AF: 0.0670 AC: 11999 AN: 179080 AF XY: 0.0587

Gnomad AFR exome AF: 0.441

Gnomad AMR exome AF: 0.0350

Gnomad ASJ exome AF: 0.0145

Gnomad EAS exome AF: 0.0962

Gnomad FIN exome AF: 0.0283

Gnomad NFE exome AF: 0.0185

Gnomad OTH exome AF: 0.0464

GnomAD4 exome AF: 0.0358 AC: 38667 AN: 1080756 Hom.: 2408 Cov.: 28 AF XY: 0.0352 AC XY: 12276 AN XY: 348276

African (AFR) AF: 0.432 AC: 11119 AN: 25759

American (AMR) AF: 0.0391 AC: 1372 AN: 35064

Ashkenazi Jewish (ASJ) AF: 0.0183 AC: 351 AN: 19143

East Asian (EAS) AF: 0.0887 AC: 2671 AN: 30106

South Asian (SAS) AF: 0.0950 AC: 5061 AN: 53285

European-Finnish (FIN) AF: 0.0277 AC: 1122 AN: 40443

Middle Eastern (MID) AF: 0.0585 AC: 232 AN: 3966

European-Non Finnish (NFE) AF: 0.0167 AC: 13825 AN: 827524

Other (OTH) AF: 0.0641 AC: 2914 AN: 45466

GnomAD4 genome AF: 0.141 AC: 15431 AN: 109818 Hom.: 2127 Cov.: 21 AF XY: 0.130 AC XY: 4185 AN XY: 32130

African (AFR) AF: 0.424 AC: 12690 AN: 29906

American (AMR) AF: 0.0710 AC: 731 AN: 10295

Ashkenazi Jewish (ASJ) AF: 0.0156 AC: 41 AN: 2620

East Asian (EAS) AF: 0.0974 AC: 336 AN: 3450

South Asian (SAS) AF: 0.104 AC: 266 AN: 2548

European-Finnish (FIN) AF: 0.0254 AC: 149 AN: 5868

Middle Eastern (MID) AF: 0.0837 AC: 18 AN: 215

European-Non Finnish (NFE) AF: 0.0191 AC: 1006 AN: 52744

Other (OTH) AF: 0.127 AC: 190 AN: 1494

Alfa AF: 0.117 Hom.: 3495

Bravo AF: 0.159

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	-0.96
CADD	Benign	1.1
DANN	Benign	0.46
PhyloP100		-0.87
Mutation Taster		=98/2	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: rs1126744; hg19: chrX-54476104; COSMIC: COSV64309403; COSMIC: COSV64309403;