rs375328916

Variant names:

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_StrongBP6_Very_StrongBP7BS2

The NM_004463.3(FGD1):c.2619C>T(p.Phe873Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000141 in 1,209,196 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 7 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., 1 hem., cov: 23)

Exomes 𝑓: 0.000010 ( 0 hom. 6 hem. )

Consequence

FGD1
NM_004463.3 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.470

Publications

2 publications found

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 Gene-Disease associations (from GenCC):

Diamond-Blackfan anemia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Diamond-Blackfan anemia 14 with mandibulofacial dysostosis
Inheritance: XL Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

TSR2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -17 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.59).

BP6

Variant X-54446376-G-A is Benign according to our data. Variant chrX-54446376-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 585860.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.47 with no splicing effect.

BS2

High AC in GnomAd4 at 6 AD,XL gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGD1	NM_004463.3 link	c.2619C>T	p.Phe873Phe	synonymous_variant	Exon 18 of 18	ENST00000375135.4	NP_004454.2	P98174A0A024R9Y5
TSR2	NM_058163.3 link	c.*1826G>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.2619C>T	p.Phe873Phe	synonymous_variant	Exon 18 of 18	1	NM_004463.3	ENSP00000364277.3		P98174
TSR2	ENST00000375151.5 link	c.*1826G>A		3_prime_UTR_variant	Exon 5 of 5	1	NM_058163.3	ENSP00000364293.4		Q969E8

Frequencies

GnomAD3 genomes

AF:

0.0000534

AC:

AN:

112315

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000194

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000337

AC:

AN:

177843

AF XY:

0.0000632

show subpopulations

Gnomad AFR exome

AF:

0.000157

Gnomad AMR exome

AF:

0.0000739

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000100

AC:

AN:

1096881

Hom.:

Cov.:

AF XY:

0.0000166

AC XY:

AN XY:

362335

show subpopulations

African (AFR)

AF:

0.0000758

AC:

AN:

26393

American (AMR)

AF:

0.0000854

AC:

AN:

35117

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19340

East Asian (EAS)

AF:

0.0000331

AC:

AN:

30189

South Asian (SAS)

AF:

0.0000745

AC:

AN:

53687

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40407

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4126

European-Non Finnish (NFE)

AF:

0.00000119

AC:

AN:

841587

Other (OTH)

AF:

0.00

AC:

AN:

46035

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000534

AC:

AN:

112315

Hom.:

Cov.:

AF XY:

0.0000290

AC XY:

AN XY:

34501

show subpopulations

African (AFR)

AF:

0.000194

AC:

AN:

30923

American (AMR)

AF:

0.00

AC:

AN:

10648

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2657

East Asian (EAS)

AF:

0.00

AC:

AN:

3543

South Asian (SAS)

AF:

0.00

AC:

AN:

2723

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6198

Middle Eastern (MID)

AF:

0.00

AC:

AN:

238

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53185

Other (OTH)

AF:

0.00

AC:

AN:

1514

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.455

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000378

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Mar 27, 2018

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 03, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

Dec 06, 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.59

CADD

Benign

1.8

(source)

DANN

Benign

0.87

PhyloP100

0.47

Mutation Taster

=100/0

polymorphism

(source)

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

Publications

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rs375328916

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over