dbSNP rs756586058: FGD1:p.Pro175HisfsTer39 (chrX-54470714-TGGGG-T) – ACMG Classification: Pathogenic (10 pts)

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1PM2

The NM_004463.3(FGD1):c.524_527delCCCC(p.Pro175HisfsTer39) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000556 in 179,906 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 19)

Exomes 𝑓: 0.0000056 ( 0 hom. 0 hem. )

Consequence

FGD1
NM_004463.3 frameshift

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.23

Publications

0 publications found

Variant links:

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]

FGD1 Gene-Disease associations (from GenCC):

Aarskog-Scott syndrome, X-linked
Inheritance: AD, XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P, ClinGen

FGD1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 10 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGD1	NM_004463.3 link	c.524_527delCCCC	p.Pro175HisfsTer39	frameshift_variant	Exon 3 of 18	ENST00000375135.4	NP_004454.2	P98174A0A024R9Y5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FGD1	ENST00000375135.4 link	c.524_527delCCCC	p.Pro175HisfsTer39	frameshift_variant	Exon 3 of 18	1	NM_004463.3	ENSP00000364277.3		P98174

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000556

AC:

AN:

179906

Hom.:

AF XY:

0.00

AC XY:

AN XY:

37592

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

5667

American (AMR)

AF:

0.00

AC:

AN:

7068

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

4754

East Asian (EAS)

AF:

0.00

AC:

AN:

10154

South Asian (SAS)

AF:

0.00

AC:

AN:

9865

European-Finnish (FIN)

AF:

0.00

AC:

AN:

13487

Middle Eastern (MID)

AF:

0.00

AC:

AN:

925

European-Non Finnish (NFE)

AF:

0.00000840

AC:

AN:

119069

Other (OTH)

AF:

0.00

AC:

AN:

8917

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

2.2

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over