NM_004463.3:c.2784dupG

Variant names:

• chrX-54446210-G-GC
• NM_004463.3:c.2784dupG

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PVS1_Moderate PM2

The NM_004463.3(FGD1):​c.2784dupG​(p.Pro929AlafsTer5) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: FGD1 NM_004463.3 frameshift
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.474

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 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 0.0353 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGD1	NM_004463.3	c.2784dupG	p.Pro929AlafsTer5	frameshift_variant	Exon 18 of 18	ENST00000375135.4	NP_004454.2
TSR2	NM_058163.3	c.*1664dupC		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.2784dupG	p.Pro929AlafsTer5	frameshift_variant	Exon 18 of 18	1	NM_004463.3	ENSP00000364277.3
TSR2	ENST00000375151.5	c.*1664dupC		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: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Aarskog syndrome Uncertain:1

May 17, 2023

MVZ Medizinische Genetik Mainz

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG Criteria: PVS1_MOD,PM2_SUP -

Computational scores

Source: dbNSFP v4.3

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.

Other links and lift over

hg19: chrX-54472643;