NM_004463.3:c.2015+48G>C

Variant names:

• chrX-54455400-C-G
• rs3830137
• NM_004463.3:c.2015+48G>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.2015+48G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.205 in 1,023,584 control chromosomes in the GnomAD database, including 27,486 homozygotes. There are 61,737 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.37 (9193 hom., 11931 hem., cov: 23)
  • Exomes 𝑓: 0.19 (18293 hom. 49806 hem.)
• Consequence: FGD1 NM_004463.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.141
• Publications: 4 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=-0.98).
• BP6: Variant X-54455400-C-G is Benign according to our data. Variant chrX-54455400-C-G is described in ClinVar as Benign. ClinVar VariationId is 259403.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.831 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FGD1	NM_004463.3	MANE Select	c.2015+48G>C		intron	N/A	NP_004454.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FGD1	ENST00000375135.4	TSL:1 MANE Select	c.2015+48G>C		intron	N/A	ENSP00000364277.3

Frequencies

GnomAD3 genomes AF: 0.366 AC: 40741 AN: 111400 Hom.: 9188 Cov.: 23

Gnomad AFR AF: 0.840

Gnomad AMI AF: 0.0472

Gnomad AMR AF: 0.354

Gnomad ASJ AF: 0.104

Gnomad EAS AF: 0.582

Gnomad SAS AF: 0.272

Gnomad FIN AF: 0.122

Gnomad MID AF: 0.199

Gnomad NFE AF: 0.133

Gnomad OTH AF: 0.342

GnomAD2 exomes AF: 0.269 AC: 43883 AN: 163058 AF XY: 0.242

Gnomad AFR exome AF: 0.853

Gnomad AMR exome AF: 0.363

Gnomad ASJ exome AF: 0.115

Gnomad EAS exome AF: 0.579

Gnomad FIN exome AF: 0.131

Gnomad NFE exome AF: 0.131

Gnomad OTH exome AF: 0.208

GnomAD4 exome AF: 0.185 AC: 168877 AN: 912129 Hom.: 18293 Cov.: 16 AF XY: 0.192 AC XY: 49806 AN XY: 259181

African (AFR) AF: 0.854 AC: 19510 AN: 22839

American (AMR) AF: 0.366 AC: 12426 AN: 33907

Ashkenazi Jewish (ASJ) AF: 0.116 AC: 2096 AN: 18134

East Asian (EAS) AF: 0.600 AC: 17445 AN: 29085

South Asian (SAS) AF: 0.260 AC: 12824 AN: 49267

European-Finnish (FIN) AF: 0.133 AC: 5288 AN: 39851

Middle Eastern (MID) AF: 0.207 AC: 780 AN: 3768

European-Non Finnish (NFE) AF: 0.132 AC: 89067 AN: 675137

Other (OTH) AF: 0.235 AC: 9441 AN: 40141

GnomAD4 genome AF: 0.366 AC: 40792 AN: 111455 Hom.: 9193 Cov.: 23 AF XY: 0.355 AC XY: 11931 AN XY: 33651

African (AFR) AF: 0.840 AC: 25660 AN: 30546

American (AMR) AF: 0.353 AC: 3699 AN: 10469

Ashkenazi Jewish (ASJ) AF: 0.104 AC: 276 AN: 2642

East Asian (EAS) AF: 0.582 AC: 2036 AN: 3501

South Asian (SAS) AF: 0.270 AC: 723 AN: 2673

European-Finnish (FIN) AF: 0.122 AC: 749 AN: 6140

Middle Eastern (MID) AF: 0.207 AC: 45 AN: 217

European-Non Finnish (NFE) AF: 0.133 AC: 7054 AN: 53072

Other (OTH) AF: 0.341 AC: 518 AN: 1517

Alfa AF: 0.226 Hom.: 2309

Bravo AF: 0.408

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

May 11, 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

not specified Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	3.8
DANN	Benign	0.48
PhyloP100		0.14
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: rs3830137; hg19: chrX-54481833; COSMIC: COSV104426814;