Genetic Variant NM_004463.3:c.2816A>G (chrX-54446179-T-C) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2PP2BP4_Moderate

The NM_004463.3(FGD1):c.2816A>G(p.Glu939Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000911 in 1,097,432 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 22)

Exomes 𝑓: 9.1e-7 ( 0 hom. 0 hem. )

Consequence

FGD1
NM_004463.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.16

Variant links:

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 links:

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]

TSR2 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in the FGD1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 11 curated pathogenic missense variants (we use a threshold of 10). The gene has 24 curated benign missense variants. Gene score misZ: 3.5183 (above the threshold of 3.09). GenCC associations: The gene is linked to Aarskog-Scott syndrome, X-linked.

BP4

Computational evidence support a benign effect (MetaRNN=0.10319978).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGD1	NM_004463.3 link	c.2816A>G	p.Glu939Gly	missense_variant	Exon 18 of 18	ENST00000375135.4	NP_004454.2	P98174A0A024R9Y5
TSR2	NM_058163.3 link	c.*1629T>C		3_prime_UTR_variant	Exon 5 of 5	ENST00000375151.5	NP_477511.1	Q969E8A0A024R9U9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FGD1	ENST00000375135.4 link	c.2816A>G	p.Glu939Gly	missense_variant	Exon 18 of 18	1	NM_004463.3	ENSP00000364277.3		P98174
TSR2	ENST00000375151.5 link	c.*1629T>C		3_prime_UTR_variant	Exon 5 of 5	1	NM_058163.3	ENSP00000364293.4		Q969E8

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

9.11e-7

AC:

AN:

1097432

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

362840

show subpopulations

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:

0.00000119

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.55

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.12

FATHMM_MKL

Benign

0.57

LIST_S2

Benign

0.76

M_CAP

Benign

0.051

MetaRNN

Benign

0.10

MetaSVM

Benign

-0.85

MutationAssessor

Benign

0.69

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-1.9

REVEL

Benign

0.16

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0070

Polyphen

0.0

Vest4

0.22

MutPred

0.094

Gain of relative solvent accessibility (P = 0.09);

MVP

0.52

MPC

2.3

ClinPred

0.70

GERP RS

5.3

Varity_R

0.26

gMVP

0.30

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over