X-54446190-C-G

Variant names:

• chrX-54446190-C-G
• rs776004329
• NM_004463.3:c.2805G>C

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.2805G>C​(p.Arg935Ser) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R935G) has been classified 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: Not reported in ClinVar
• Conservation: PhyloP100: 2.08
• 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: 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=0.06346294).

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.2805G>C	p.Arg935Ser	missense	Exon 18 of 18	NP_004454.2
	TSR2	NM_058163.3	MANE Select	c.*1640C>G		3_prime_UTR	Exon 5 of 5	NP_477511.1	Q969E8
	TSR2	NM_001346789.2		c.*1640C>G		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.2805G>C	p.Arg935Ser	missense	Exon 18 of 18	ENSP00000364277.3	P98174
	TSR2	ENST00000375151.5	TSL:1 MANE Select	c.*1640C>G		3_prime_UTR	Exon 5 of 5	ENSP00000364293.4	Q969E8
	FGD1	ENST00000934021.1		c.2805G>C	p.Arg935Ser	missense	Exon 19 of 19	ENSP00000604080.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD2 exomes AF: 0.00000554 AC: 1 AN: 180514 AF XY: 0.0000153

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000124

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 9.11e-7 AC: 1 AN: 1097530 Hom.: 0 Cov.: 31 AF XY: 0.00000276 AC XY: 1 AN XY: 362938

African (AFR) AF: 0.00 AC: 0 AN: 26400

American (AMR) AF: 0.00 AC: 0 AN: 35163

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19367

East Asian (EAS) AF: 0.00 AC: 0 AN: 30193

South Asian (SAS) AF: 0.00 AC: 0 AN: 53951

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40468

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4121

European-Non Finnish (NFE) AF: 0.00000119 AC: 1 AN: 841808

Other (OTH) AF: 0.00 AC: 0 AN: 46059

GnomAD4 genome Cov.: 23

ExAC AF: 0.0000165 AC: 2

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.065	T
FATHMM_MKL	Benign	0.70	D
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.063	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N
PhyloP100		2.1
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.59	N
REVEL	Benign	0.035
Sift	Benign	0.035	D
Sift4G	Benign	0.63	T
Polyphen		0.0010	B
Vest4		0.18
MutPred		0.14		Gain of phosphorylation at R935 (P = 0.017)
MVP		0.38
MPC		1.3
ClinPred		0.084	T
GERP RS		2.6
Varity_R		0.18
gMVP		0.33
Mutation Taster		=91/9	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: rs776004329; hg19: chrX-54472623;