rs138723423

Variant names:

• chrX-54470441-C-T
• rs138723423
• NM_004463.3:c.676G>A

Your query was ambiguous. Multiple possible variants found:

• chrX-54470441-C-T
• chrX-54470441-C-G

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_004463.3(FGD1):​c.676G>A​(p.Ala226Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00321 in 1,203,728 control chromosomes in the GnomAD database, including 8 homozygotes. There are 1,169 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0025 (0 hom., 99 hem., cov: 23)
  • Exomes 𝑓: 0.0033 (8 hom. 1070 hem.)
• Consequence: FGD1 NM_004463.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.0210
• 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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004192412).
• BP6: Variant X-54470441-C-T is Benign according to our data. Variant chrX-54470441-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 95094.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 281 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.676G>A	p.Ala226Thr	missense	Exon 4 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.676G>A	p.Ala226Thr	missense	Exon 4 of 18	ENSP00000364277.3	P98174
	FGD1	ENST00000934021.1		c.676G>A	p.Ala226Thr	missense	Exon 4 of 19	ENSP00000604080.1
	FGD1	ENST00000934019.1		c.676G>A	p.Ala226Thr	missense	Exon 4 of 18	ENSP00000604078.1

Frequencies

GnomAD3 genomes AF: 0.00252 AC: 281 AN: 111497 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.000457

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00653

Gnomad ASJ AF: 0.000378

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000375

Gnomad FIN AF: 0.00362

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00323

Gnomad OTH AF: 0.00201

GnomAD2 exomes AF: 0.00268 AC: 463 AN: 172713 AF XY: 0.00212

Gnomad AFR exome AF: 0.000250

Gnomad AMR exome AF: 0.00288

Gnomad ASJ exome AF: 0.000814

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00460

Gnomad NFE exome AF: 0.00383

Gnomad OTH exome AF: 0.00371

GnomAD4 exome AF: 0.00328 AC: 3581 AN: 1092179 Hom.: 8 Cov.: 32 AF XY: 0.00297 AC XY: 1070 AN XY: 359709

African (AFR) AF: 0.000304 AC: 8 AN: 26352

American (AMR) AF: 0.00265 AC: 93 AN: 35133

Ashkenazi Jewish (ASJ) AF: 0.00103 AC: 20 AN: 19342

East Asian (EAS) AF: 0.00 AC: 0 AN: 30119

South Asian (SAS) AF: 0.0000932 AC: 5 AN: 53653

European-Finnish (FIN) AF: 0.00441 AC: 160 AN: 36257

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4133

European-Non Finnish (NFE) AF: 0.00375 AC: 3157 AN: 841219

Other (OTH) AF: 0.00300 AC: 138 AN: 45971

GnomAD4 genome AF: 0.00252 AC: 281 AN: 111549 Hom.: 0 Cov.: 23 AF XY: 0.00293 AC XY: 99 AN XY: 33775

African (AFR) AF: 0.000456 AC: 14 AN: 30697

American (AMR) AF: 0.00653 AC: 69 AN: 10573

Ashkenazi Jewish (ASJ) AF: 0.000378 AC: 1 AN: 2648

East Asian (EAS) AF: 0.00 AC: 0 AN: 3497

South Asian (SAS) AF: 0.000376 AC: 1 AN: 2657

European-Finnish (FIN) AF: 0.00362 AC: 22 AN: 6074

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 216

European-Non Finnish (NFE) AF: 0.00323 AC: 171 AN: 52998

Other (OTH) AF: 0.00199 AC: 3 AN: 1511

Alfa AF: 0.00300 Hom.: 133

Bravo AF: 0.00252

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.00381 AC: 11

ESP6500AA AF: 0.000523 AC: 2

ESP6500EA AF: 0.00343 AC: 23

ExAC AF: 0.00231 AC: 280

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not provided (6)
-	-	1	FGD1-related disorder (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	Intellectual disability (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.77	T
BayesDel_noAF	Benign	-0.88
CADD	Benign	10
DANN	Uncertain	0.98
DEOGEN2	Benign	0.066	T
FATHMM_MKL	Benign	0.029	N
LIST_S2	Benign	0.65	T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.0042	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N
PhyloP100		-0.021
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-0.49	N
REVEL	Benign	0.036
Sift	Benign	0.19	T
Sift4G	Benign	0.78	T
Polyphen		0.012	B
Vest4		0.017
MVP		0.28
MPC		0.30
ClinPred		0.011	T
GERP RS		1.5
Varity_R		0.048
gMVP		0.12
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs138723423; hg19: chrX-54496874;