X-54446234-G-A

Variant names:

• chrX-54446234-G-A
• rs869312743
• NM_004463.3:c.2761C>T

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PVS1_Moderate PM2 PP5

The NM_004463.3(FGD1):​c.2761C>T​(p.Arg921*) 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. R921R) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 23)
• Consequence: FGD1 NM_004463.3 stop_gained
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 3.01
• Publications: 4 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: Uncertain_significance. The variant received 5 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 0.0433 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-54446234-G-A is Pathogenic according to our data. Variant chrX-54446234-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 224655.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGD1	NM_004463.3	c.2761C>T	p.Arg921*	stop_gained	Exon 18 of 18	ENST00000375135.4	NP_004454.2
TSR2	NM_058163.3	c.*1684G>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.2761C>T	p.Arg921*	stop_gained	Exon 18 of 18	1	NM_004463.3	ENSP00000364277.3
TSR2	ENST00000375151.5	c.*1684G>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

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1

Jun 25, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nonsense variant predicted to result in protein truncation as the last 41 amino acids are lost, although loss-of-function variants have not been reported downstream of this position in the protein; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 34189097, 33762894, 27551683, 33482836) -

Aarskog syndrome Uncertain:1

Mar 15, 2016

Keegan Laboratory, University of Michigan

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing;research

Based on ACMG guidelines, criteria met are PM2, PP1, PP3, and PP4. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	38
DANN	Uncertain	1.0
FATHMM_MKL	Uncertain	0.88	D
PhyloP100		3.0
Vest4		0.76
GERP RS		5.8
Mutation Taster		=11/189	disease causing

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

Other links and lift over

dbSNP: rs869312743; hg19: chrX-54472667; COSMIC: COSV64309450; COSMIC: COSV64309450;