rs1269514277

Variant names:

• chrX-54446267-G-A
• rs1269514277
• NM_004463.3:c.2728C>T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1_Moderate PM2 PP5_Very_Strong

The NM_004463.3(FGD1):​c.2728C>T​(p.Arg910*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: FGD1 NM_004463.3 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 2.72
• Publications: 1 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]

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

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0547 CDS is truncated, and there are 3 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-54446267-G-A is Pathogenic according to our data. Variant chrX-54446267-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 547370.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGD1	NM_004463.3	c.2728C>T	p.Arg910*	stop_gained	Exon 18 of 18	ENST00000375135.4	NP_004454.2
TSR2	NM_058163.3	c.*1717G>A		3_prime_UTR_variant	Exon 5 of 5	ENST00000375151.5	NP_477511.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FGD1	ENST00000375135.4	c.2728C>T	p.Arg910*	stop_gained	Exon 18 of 18	1	NM_004463.3	ENSP00000364277.3
TSR2	ENST00000375151.5	c.*1717G>A		3_prime_UTR_variant	Exon 5 of 5	1	NM_058163.3	ENSP00000364293.4

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 23

Alfa AF: 0.000142 Hom.: 1

Bravo AF: 0.00000756

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Aarskog syndrome Pathogenic:2

May 08, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 01, 2016

Center for Human Genetics, Inc, Center for Human Genetics, Inc

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

FGD1-related disorder Pathogenic:1

Sep 03, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The FGD1 c.2728C>T variant is predicted to result in premature protein termination (p.Arg910*). To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0093% of alleles in individuals of European (non-Finnish) descent in gnomAD. This variant is located at the terminal exon in FGD1; however, a downstream truncating variant c.2761C>T (p.Arg921*) has been documented in two unrelated individuals with Aarskog-Scott syndrome, including one de novo case (Griffin et al. 2016. PubMed ID: 27551683; Meyer et al. 2021. PubMed ID: 33482836). Taken together, the c.2728C>T (p.Arg910*) variant is interpreted as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.71	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	37
DANN	Uncertain	1.0
FATHMM_MKL	Uncertain	0.77	D
PhyloP100		2.7
Vest4		0.69
GERP RS		4.8
Mutation Taster		=10/190	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1269514277; hg19: chrX-54472700;