X-54446141-G-C

Variant names:

• chrX-54446141-G-C
• rs374402628
• NM_004463.3:c.2854C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_004463.3(FGD1):​c.2854C>G​(p.Pro952Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.1e-7 (0 hom. 1 hem.)
  • Failed GnomAD Quality Control
• Consequence: FGD1 NM_004463.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.487
• Publications: 0 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: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.058905125).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004463.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FGD1	NM_004463.3	MANE Select	c.2854C>G	p.Pro952Ala	missense	Exon 18 of 18	NP_004454.2
	TSR2	NM_058163.3	MANE Select	c.*1591G>C		3_prime_UTR	Exon 5 of 5	NP_477511.1	Q969E8
	TSR2	NM_001346789.2		c.*1591G>C		3_prime_UTR	Exon 5 of 5	NP_001333718.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FGD1	ENST00000375135.4	TSL:1 MANE Select	c.2854C>G	p.Pro952Ala	missense	Exon 18 of 18	ENSP00000364277.3	P98174
	TSR2	ENST00000375151.5	TSL:1 MANE Select	c.*1591G>C		3_prime_UTR	Exon 5 of 5	ENSP00000364293.4	Q969E8
	FGD1	ENST00000934021.1		c.2854C>G	p.Pro952Ala	missense	Exon 19 of 19	ENSP00000604080.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 9.11e-7 AC: 1 AN: 1097347 Hom.: 0 Cov.: 31 AF XY: 0.00000276 AC XY: 1 AN XY: 362775

African (AFR) AF: 0.00 AC: 0 AN: 26378

American (AMR) AF: 0.0000285 AC: 1 AN: 35108

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19360

East Asian (EAS) AF: 0.00 AC: 0 AN: 30187

South Asian (SAS) AF: 0.00 AC: 0 AN: 53973

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40452

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4053

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 841811

Other (OTH) AF: 0.00 AC: 0 AN: 46025

GnomAD4 genome Cov.: 23

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.051
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	9.4
DANN	Uncertain	0.98
DEOGEN2	Benign	0.082	T
FATHMM_MKL	Benign	0.043	N
LIST_S2	Benign	0.59	T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.059	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N
PhyloP100		0.49
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.22
Sift	Uncertain	0.017	D
Sift4G	Benign	0.15	T
Polyphen		0.0	B
Vest4		0.16
MutPred		0.065		Loss of glycosylation at P952 (P = 0.0113)
MVP		0.32
MPC		1.8
ClinPred		0.071	T
GERP RS		3.3
Varity_R		0.059
gMVP		0.29
Mutation Taster		=99/1	polymorphism

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: rs374402628; hg19: chrX-54472574;