X-54446242-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PP2 BP4

The NM_004463.3(FGD1):c.2753G>A(p.Arg918Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000146 in 1,097,701 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 5 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.000015 (0 hom. 5 hem.)
• Consequence: FGD1 NM_004463.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.74

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]

TSR2 (HGNC:25455): (TSR2 ribosome maturation factor) The protein encoded by this gene appears to repress the transcription of NF-kappaB and may be involved in apoptosis. Defects in this gene are a cause of Diamond-Blackfan anemia. [provided by RefSeq, Oct 2016]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PP2: Missense variant where missense usually causes diseases, FGD1
• BP4: Computational evidence support a benign effect (MetaRNN=0.2773967).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FGD1	NM_004463.3	c.2753G>A	p.Arg918Gln	missense_variant	18/18	ENST00000375135.4
TSR2	NM_058163.3	c.*1692C>T		3_prime_UTR_variant	5/5	ENST00000375151.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FGD1	ENST00000375135.4	c.2753G>A	p.Arg918Gln	missense_variant	18/18	1	NM_004463.3	P1
TSR2	ENST00000375151.5	c.*1692C>T		3_prime_UTR_variant	5/5	1	NM_058163.3	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD3 exomes AF: 0.0000111 AC: 2 AN: 180889 Hom.: 0 AF XY: 0.0000152 AC XY: 1 AN XY: 65707

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000124

Gnomad OTH exome AF: 0.000225

GnomAD4 exome AF: 0.0000146 AC: 16 AN: 1097701 Hom.: 0 Cov.: 31 AF XY: 0.0000138 AC XY: 5 AN XY: 363099

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000178

Gnomad4 OTH exome AF: 0.0000217

GnomAD4 genome Cov.: 23

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 07, 2023

The c.2753G>A (p.R918Q) alteration is located in exon 18 (coding exon 18) of the FGD1 gene. This alteration results from a G to A substitution at nucleotide position 2753, causing the arginine (R) at amino acid position 918 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.56
Cadd	Benign	23
Dann	Uncertain	1.0
DEOGEN2	Benign	0.32	T
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.28	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L
MutationTaster	Benign	0.98	D
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.099
Sift	Benign	0.29	T
Sift4G	Benign	0.59	T
Polyphen		0.30	B
Vest4		0.14
MutPred		0.50		Loss of MoRF binding (P = 0.0262);
MVP		0.63
MPC		2.0
ClinPred		0.32	T
GERP RS		5.8
Varity_R		0.18
gMVP		0.79

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

Publications

LitVar

Other links and lift over

dbSNP: rs767928682; hg19: chrX-54472675;