chrX-54446179-T-G

Variant names:

• chrX-54446179-T-G
• rs147012050
• NM_004463.3:c.2816A>C

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_004463.3(FGD1):​c.2816A>C​(p.Glu939Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000208 in 1,209,504 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 74 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00049 (0 hom., 15 hem., cov: 22)
  • Exomes 𝑓: 0.00018 (0 hom. 59 hem.)
• Consequence: FGD1 NM_004463.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 3.16
• 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: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009158999).
• BP6: Variant X-54446179-T-G is Benign according to our data. Variant chrX-54446179-T-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 287068.
• BS2: High AC in GnomAd4 at 55 AD,XL gene.

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.2816A>C	p.Glu939Ala	missense	Exon 18 of 18	NP_004454.2
	TSR2	NM_058163.3	MANE Select	c.*1629T>G		3_prime_UTR	Exon 5 of 5	NP_477511.1	Q969E8
	TSR2	NM_001346789.2		c.*1629T>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.2816A>C	p.Glu939Ala	missense	Exon 18 of 18	ENSP00000364277.3	P98174
	TSR2	ENST00000375151.5	TSL:1 MANE Select	c.*1629T>G		3_prime_UTR	Exon 5 of 5	ENSP00000364293.4	Q969E8
	FGD1	ENST00000934021.1		c.2816A>C	p.Glu939Ala	missense	Exon 19 of 19	ENSP00000604080.1

Frequencies

GnomAD3 genomes AF: 0.000473 AC: 53 AN: 112021 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.00130

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000283

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00198

GnomAD2 exomes AF: 0.000250 AC: 45 AN: 180227 AF XY: 0.000215

Gnomad AFR exome AF: 0.00132

Gnomad AMR exome AF: 0.000404

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000199

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000179 AC: 196 AN: 1097432 Hom.: 0 Cov.: 31 AF XY: 0.000163 AC XY: 59 AN XY: 362840

African (AFR) AF: 0.00220 AC: 58 AN: 26394

American (AMR) AF: 0.000541 AC: 19 AN: 35149

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19361

East Asian (EAS) AF: 0.00 AC: 0 AN: 30197

South Asian (SAS) AF: 0.000111 AC: 6 AN: 53948

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40464

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4113

European-Non Finnish (NFE) AF: 0.000113 AC: 95 AN: 841754

Other (OTH) AF: 0.000391 AC: 18 AN: 46052

GnomAD4 genome AF: 0.000491 AC: 55 AN: 112072 Hom.: 0 Cov.: 22 AF XY: 0.000438 AC XY: 15 AN XY: 34272

African (AFR) AF: 0.00136 AC: 42 AN: 30830

American (AMR) AF: 0.000282 AC: 3 AN: 10620

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2642

East Asian (EAS) AF: 0.00 AC: 0 AN: 3529

South Asian (SAS) AF: 0.00 AC: 0 AN: 2704

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6172

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 218

European-Non Finnish (NFE) AF: 0.000132 AC: 7 AN: 53136

Other (OTH) AF: 0.00196 AC: 3 AN: 1534

Alfa AF: 0.000260 Hom.: 4

Bravo AF: 0.000612

ESP6500AA AF: 0.000782 AC: 3

ESP6500EA AF: 0.000297 AC: 2

ExAC AF: 0.000264 AC: 32

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	not provided (3)
-	-	1	FGD1-related disorder (1)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.12	T
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.049	D
MetaRNN	Benign	0.0092	T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	0.69	N
PhyloP100		3.2
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.12
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.019	D
Polyphen		0.0050	B
Vest4		0.23
MVP		0.59
MPC		2.0
ClinPred		0.059	T
GERP RS		5.3
Varity_R		0.26
gMVP		0.35
Mutation Taster		=88/12	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: rs147012050; hg19: chrX-54472612;