chrX-54465430-G-A

Variant names:

• chrX-54465430-G-A
• rs2071812
• NM_004463.3:c.1636+21C>T

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.1636+21C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00938 in 1,196,170 control chromosomes in the GnomAD database, including 291 homozygotes. There are 3,733 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (39 hom., 418 hem., cov: 21)
  • Exomes 𝑓: 0.0091 (252 hom. 3315 hem.)
• Consequence: FGD1 NM_004463.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.67
• Publications: 2 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=-0.78).
• BP6: Variant X-54465430-G-A is Benign according to our data. Variant chrX-54465430-G-A is described in ClinVar as Benign. ClinVar VariationId is 259402.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0981 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.1636+21C>T		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.1636+21C>T		intron	N/A	ENSP00000364277.3

Frequencies

GnomAD3 genomes AF: 0.0121 AC: 1328 AN: 110050 Hom.: 39 Cov.: 21

Gnomad AFR AF: 0.00382

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0632

Gnomad ASJ AF: 0.000380

Gnomad EAS AF: 0.107

Gnomad SAS AF: 0.0218

Gnomad FIN AF: 0.00378

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00167

Gnomad OTH AF: 0.0228

GnomAD2 exomes AF: 0.0265 AC: 4534 AN: 171389 AF XY: 0.0228

Gnomad AFR exome AF: 0.00354

Gnomad AMR exome AF: 0.0829

Gnomad ASJ exome AF: 0.00239

Gnomad EAS exome AF: 0.112

Gnomad FIN exome AF: 0.00305

Gnomad NFE exome AF: 0.00209

Gnomad OTH exome AF: 0.0155

GnomAD4 exome AF: 0.00911 AC: 9893 AN: 1086067 Hom.: 252 Cov.: 30 AF XY: 0.00935 AC XY: 3315 AN XY: 354671

African (AFR) AF: 0.00183 AC: 48 AN: 26222

American (AMR) AF: 0.0834 AC: 2897 AN: 34732

Ashkenazi Jewish (ASJ) AF: 0.00184 AC: 34 AN: 18513

East Asian (EAS) AF: 0.103 AC: 3086 AN: 30057

South Asian (SAS) AF: 0.0258 AC: 1342 AN: 52016

European-Finnish (FIN) AF: 0.00345 AC: 138 AN: 40024

Middle Eastern (MID) AF: 0.00295 AC: 12 AN: 4061

European-Non Finnish (NFE) AF: 0.00210 AC: 1754 AN: 834847

Other (OTH) AF: 0.0128 AC: 582 AN: 45595

GnomAD4 genome AF: 0.0121 AC: 1330 AN: 110103 Hom.: 39 Cov.: 21 AF XY: 0.0129 AC XY: 418 AN XY: 32387

African (AFR) AF: 0.00381 AC: 116 AN: 30412

American (AMR) AF: 0.0634 AC: 654 AN: 10308

Ashkenazi Jewish (ASJ) AF: 0.000380 AC: 1 AN: 2633

East Asian (EAS) AF: 0.107 AC: 361 AN: 3366

South Asian (SAS) AF: 0.0215 AC: 54 AN: 2512

European-Finnish (FIN) AF: 0.00378 AC: 22 AN: 5823

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 211

European-Non Finnish (NFE) AF: 0.00167 AC: 88 AN: 52659

Other (OTH) AF: 0.0225 AC: 34 AN: 1508

Alfa AF: 0.00577 Hom.: 44

Bravo AF: 0.0188

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

May 20, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	-0.78
CADD	Benign	5.1
DANN	Benign	0.67
PhyloP100		1.7
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: rs2071812; hg19: chrX-54491863; COSMIC: COSV64309480;