rs146079207

Variant names:

• chrX-54469996-C-G
• rs146079207
• NM_004463.3:c.1101+20G>C

Your query was ambiguous. Multiple possible variants found:

• chrX-54469996-C-G
• chrX-54469996-C-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004463.3(FGD1):​c.1101+20G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00214 in 1,195,728 control chromosomes in the GnomAD database, including 40 homozygotes. There are 664 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (17 hom., 329 hem., cov: 22)
  • Exomes 𝑓: 0.0012 (23 hom. 335 hem.)
• Consequence: FGD1 NM_004463.3 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.58
• Publications: 0 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: XL, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet, ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BP6: Variant X-54469996-C-G is Benign according to our data. Variant chrX-54469996-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 445769.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0113 (1255/110880) while in subpopulation AFR AF = 0.0398 (1215/30520). AF 95% confidence interval is 0.0379. There are 17 homozygotes in GnomAd4. There are 329 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1255 AD,XL gene.

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.1101+20G>C		intron	N/A	NP_004454.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FGD1	ENST00000375135.4	TSL:1 MANE Select	c.1101+20G>C		intron	N/A	ENSP00000364277.3	P98174
	FGD1	ENST00000934021.1		c.1101+20G>C		intron	N/A	ENSP00000604080.1
	FGD1	ENST00000934019.1		c.1101+20G>C		intron	N/A	ENSP00000604078.1

Frequencies

GnomAD3 genomes AF: 0.0113 AC: 1251 AN: 110828 Hom.: 17 Cov.: 22

Gnomad AFR AF: 0.0398

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00268

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000379

Gnomad OTH AF: 0.00667

GnomAD2 exomes AF: 0.00314 AC: 567 AN: 180553 AF XY: 0.00195

Gnomad AFR exome AF: 0.0409

Gnomad AMR exome AF: 0.000915

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000250

Gnomad OTH exome AF: 0.00156

GnomAD4 exome AF: 0.00120 AC: 1301 AN: 1084848 Hom.: 23 Cov.: 30 AF XY: 0.000952 AC XY: 335 AN XY: 351968

African (AFR) AF: 0.0423 AC: 1108 AN: 26170

American (AMR) AF: 0.00111 AC: 39 AN: 35148

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19292

East Asian (EAS) AF: 0.00 AC: 0 AN: 30154

South Asian (SAS) AF: 0.0000745 AC: 4 AN: 53703

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40521

Middle Eastern (MID) AF: 0.00102 AC: 4 AN: 3915

European-Non Finnish (NFE) AF: 0.0000385 AC: 32 AN: 830309

Other (OTH) AF: 0.00250 AC: 114 AN: 45636

GnomAD4 genome AF: 0.0113 AC: 1255 AN: 110880 Hom.: 17 Cov.: 22 AF XY: 0.00994 AC XY: 329 AN XY: 33092

African (AFR) AF: 0.0398 AC: 1215 AN: 30520

American (AMR) AF: 0.00268 AC: 28 AN: 10457

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2630

East Asian (EAS) AF: 0.00 AC: 0 AN: 3493

South Asian (SAS) AF: 0.00 AC: 0 AN: 2474

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6065

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 219

European-Non Finnish (NFE) AF: 0.0000379 AC: 2 AN: 52826

Other (OTH) AF: 0.00658 AC: 10 AN: 1519

Alfa AF: 0.000916 Hom.: 4

Bravo AF: 0.0128

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.030
DANN	Benign	0.50
PhyloP100		-1.6
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs146079207;

hg19: chrX-54496429;