NM_004463.3:c.2821C>T

Variant names:

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP2BP4_StrongBP6_Very_StrongBS2

The NM_004463.3(FGD1):c.2821C>T(p.Pro941Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000794 in 1,209,581 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 30 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., 5 hem., cov: 23)

Exomes 𝑓: 0.000077 ( 0 hom. 25 hem. )

Consequence

FGD1
NM_004463.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.271

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 Benign. Variant got -15 ACMG points.

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=0.011383772).

BP6

Variant X-54446174-G-A is Benign according to our data. Variant chrX-54446174-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 589463.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Hemizygotes in GnomAd4 at 5 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGD1	NM_004463.3 link	c.2821C>T	p.Pro941Ser	missense_variant	Exon 18 of 18	ENST00000375135.4	NP_004454.2	P98174A0A024R9Y5
TSR2	NM_058163.3 link	c.*1624G>A		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.2821C>T	p.Pro941Ser	missense_variant	Exon 18 of 18	1	NM_004463.3	ENSP00000364277.3		P98174
TSR2	ENST00000375151.5 link	c.*1624G>A		3_prime_UTR_variant	Exon 5 of 5	1	NM_058163.3	ENSP00000364293.4		Q969E8

Frequencies

GnomAD3 genomes

AF:

0.000107

AC:

AN:

112172

Hom.:

Cov.:

AF XY:

0.000146

AC XY:

AN XY:

34348

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000282

Gnomad ASJ

AF:

0.00227

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000736

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000658

GnomAD3 exomes

AF:

0.000144

AC:

AN:

180203

Hom.:

AF XY:

0.000107

AC XY:

AN XY:

65271

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000184

Gnomad ASJ exome

AF:

0.00243

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000374

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000765

AC:

AN:

1097409

Hom.:

Cov.:

AF XY:

0.0000689

AC XY:

AN XY:

362833

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000171

Gnomad4 ASJ exome

AF:

0.00243

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000130

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000131

Gnomad4 OTH exome

AF:

0.000261

GnomAD4 genome

AF:

0.000107

AC:

AN:

112172

Hom.:

Cov.:

AF XY:

0.000146

AC XY:

AN XY:

34348

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000282

Gnomad4 ASJ

AF:

0.00227

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000736

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000658

Alfa

AF:

0.000144

Hom.:

Bravo

AF:

0.0000945

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000149

AC:

ExAC

AF:

0.000132

AC:

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Benign:1

May 18, 2018

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not provided

Benign:1

Aug 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.068

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.81

CADD

Benign

7.9

DANN

Benign

0.97

DEOGEN2

Benign

0.11

FATHMM_MKL

Benign

0.069

LIST_S2

Benign

0.67

M_CAP

Benign

0.0079

MetaRNN

Benign

0.011

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.34

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.70

REVEL

Benign

0.13

Sift

Benign

0.061

Sift4G

Benign

0.19

Polyphen

0.0

Vest4

0.088

MVP

0.38

MPC

1.2

ClinPred

0.024

GERP RS

-0.081

Varity_R

0.052

gMVP

0.16

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over