rs2230265

Variant names:

• chrX-54446073-G-A
• rs2230265
• NM_004463.3:c.*36C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004463.3(FGD1):​c.*36C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0973 in 1,118,043 control chromosomes in the GnomAD database, including 6,565 homozygotes. There are 33,846 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.086 (597 hom., 2966 hem., cov: 22)
  • Exomes 𝑓: 0.099 (5968 hom. 30880 hem.)
• Consequence: FGD1 NM_004463.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.295
• Publications: 8 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP6: Variant X-54446073-G-A is Benign according to our data. Variant chrX-54446073-G-A is described in ClinVar as Benign. ClinVar VariationId is 95076.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.452 is higher than 0.05.

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.*36C>T		3_prime_UTR	Exon 18 of 18	NP_004454.2
	TSR2	NM_058163.3	MANE Select	c.*1523G>A		3_prime_UTR	Exon 5 of 5	NP_477511.1	Q969E8
	TSR2	NM_001346789.2		c.*1523G>A		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.*36C>T		3_prime_UTR	Exon 18 of 18	ENSP00000364277.3	P98174
	TSR2	ENST00000375151.5	TSL:1 MANE Select	c.*1523G>A		3_prime_UTR	Exon 5 of 5	ENSP00000364293.4	Q969E8
	FGD1	ENST00000934021.1		c.*36C>T		3_prime_UTR	Exon 19 of 19	ENSP00000604080.1

Frequencies

GnomAD3 genomes AF: 0.0866 AC: 9621 AN: 111141 Hom.: 600 Cov.: 22

Gnomad AFR AF: 0.0158

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.220

Gnomad ASJ AF: 0.0894

Gnomad EAS AF: 0.471

Gnomad SAS AF: 0.153

Gnomad FIN AF: 0.0855

Gnomad MID AF: 0.0462

Gnomad NFE AF: 0.0742

Gnomad OTH AF: 0.0990

GnomAD2 exomes AF: 0.142 AC: 21203 AN: 149170 AF XY: 0.130

Gnomad AFR exome AF: 0.0129

Gnomad AMR exome AF: 0.286

Gnomad ASJ exome AF: 0.0897

Gnomad EAS exome AF: 0.478

Gnomad FIN exome AF: 0.0907

Gnomad NFE exome AF: 0.0748

Gnomad OTH exome AF: 0.119

GnomAD4 exome AF: 0.0985 AC: 99176 AN: 1006852 Hom.: 5968 Cov.: 20 AF XY: 0.102 AC XY: 30880 AN XY: 303936

African (AFR) AF: 0.0116 AC: 280 AN: 24158

American (AMR) AF: 0.284 AC: 8484 AN: 29890

Ashkenazi Jewish (ASJ) AF: 0.0898 AC: 1621 AN: 18051

East Asian (EAS) AF: 0.509 AC: 15046 AN: 29568

South Asian (SAS) AF: 0.147 AC: 7235 AN: 49208

European-Finnish (FIN) AF: 0.0909 AC: 3625 AN: 39875

Middle Eastern (MID) AF: 0.0723 AC: 232 AN: 3209

European-Non Finnish (NFE) AF: 0.0754 AC: 58030 AN: 770057

Other (OTH) AF: 0.108 AC: 4623 AN: 42836

GnomAD4 genome AF: 0.0864 AC: 9607 AN: 111191 Hom.: 597 Cov.: 22 AF XY: 0.0888 AC XY: 2966 AN XY: 33387

African (AFR) AF: 0.0157 AC: 484 AN: 30766

American (AMR) AF: 0.219 AC: 2300 AN: 10489

Ashkenazi Jewish (ASJ) AF: 0.0894 AC: 236 AN: 2641

East Asian (EAS) AF: 0.471 AC: 1602 AN: 3401

South Asian (SAS) AF: 0.151 AC: 390 AN: 2576

European-Finnish (FIN) AF: 0.0855 AC: 515 AN: 6024

Middle Eastern (MID) AF: 0.0459 AC: 10 AN: 218

European-Non Finnish (NFE) AF: 0.0742 AC: 3923 AN: 52888

Other (OTH) AF: 0.0977 AC: 147 AN: 1505

Alfa AF: 0.0874 Hom.: 6170

Bravo AF: 0.100

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Aarskog syndrome (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	5.0
DANN	Benign	0.84
PhyloP100		0.29
Mutation Taster		=100/0	polymorphism (auto)

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: rs2230265; hg19: chrX-54472506; COSMIC: COSV64309325; COSMIC: COSV64309325;