X-54446073-G-A

Variant summary

Our verdict is Benign. Variant got -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:3
• Conservation: PhyloP100: 0.295

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 Benign. Variant got -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FGD1	NM_004463.3	c.*36C>T		3_prime_UTR_variant	18/18	ENST00000375135.4
TSR2	NM_058163.3	c.*1523G>A		3_prime_UTR_variant	5/5	ENST00000375151.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FGD1	ENST00000375135.4	c.*36C>T		3_prime_UTR_variant	18/18	1	NM_004463.3	P1
TSR2	ENST00000375151.5	c.*1523G>A		3_prime_UTR_variant	5/5	1	NM_058163.3	P1

Frequencies

GnomAD3 genomes AF: 0.0866 AC: 9621 AN: 111141 Hom.: 600 Cov.: 22 AF XY: 0.0890 AC XY: 2967 AN XY: 33329

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

GnomAD3 exomes AF: 0.142 AC: 21203 AN: 149170 Hom.: 2085 AF XY: 0.130 AC XY: 5736 AN XY: 44280

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 SAS exome AF: 0.140

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

Gnomad4 AFR exome AF: 0.0116

Gnomad4 AMR exome AF: 0.284

Gnomad4 ASJ exome AF: 0.0898

Gnomad4 EAS exome AF: 0.509

Gnomad4 SAS exome AF: 0.147

Gnomad4 FIN exome AF: 0.0909

Gnomad4 NFE exome AF: 0.0754

Gnomad4 OTH exome AF: 0.108

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

Gnomad4 AFR AF: 0.0157

Gnomad4 AMR AF: 0.219

Gnomad4 ASJ AF: 0.0894

Gnomad4 EAS AF: 0.471

Gnomad4 SAS AF: 0.151

Gnomad4 FIN AF: 0.0855

Gnomad4 NFE AF: 0.0742

Gnomad4 OTH AF: 0.0977

Alfa AF: 0.0875 Hom.: 4409

Bravo AF: 0.100

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Mar 07, 2013

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 11, 2021

- -

Aarskog syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
Cadd	Benign	5.0
Dann	Benign	0.84

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

LitVar

Other links and lift over

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