Genetic Variant ENST00000543601.5:c.-347C>T (chr3-14819448-C-T) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The ENST00000543601.5(FGD5):c.-347C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000191 in 1,550,304 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00055 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00015 ( 0 hom. )

Consequence

FGD5
ENST00000543601.5 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.427

Publications

2 publications found

Variant links:

Genes affected

FGD5 (HGNC:19117): (FYVE, RhoGEF and PH domain containing 5) Predicted to enable guanyl-nucleotide exchange factor activity and small GTPase binding activity. Predicted to be involved in several processes, including filopodium assembly; regulation of GTPase activity; and regulation of cell shape. Located in plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

FGD5 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.011086017).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGD5	NM_152536.4 link	c.377C>T	p.Pro126Leu	missense_variant	Exon 1 of 20	ENST00000285046.10	NP_689749.3	Q6ZNL6-1A0A2X0SFF2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
FGD5	ENST00000543601.5 link	c.-347C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 19	1		ENSP00000445949.1	B7ZM68
FGD5	ENST00000285046.10 link	c.377C>T	p.Pro126Leu	missense_variant	Exon 1 of 20	1	NM_152536.4	ENSP00000285046.5	Q6ZNL6-1
FGD5	ENST00000543601.5 link	c.-347C>T		5_prime_UTR_variant	Exon 1 of 19	1		ENSP00000445949.1	B7ZM68
FGD5	ENST00000640506.1 link	c.506C>T	p.Pro169Leu	missense_variant	Exon 2 of 2	5		ENSP00000492654.1	A0A1W2PRG7

Frequencies

GnomAD3 genomes

AF:

0.000539

AC:

AN:

152118

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00167

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.000958

GnomAD2 exomes

AF:

0.000295

AC:

AN:

152542

AF XY:

0.000222

show subpopulations

Gnomad AFR exome

AF:

0.00141

Gnomad AMR exome

AF:

0.000934

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000918

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000170

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000152

AC:

213

AN:

1398068

Hom.:

Cov.:

AF XY:

0.000135

AC XY:

AN XY:

689384

show subpopulations

African (AFR)

AF:

0.00136

AC:

AN:

31582

American (AMR)

AF:

0.000785

AC:

AN:

35664

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25106

East Asian (EAS)

AF:

0.0000280

AC:

AN:

35722

South Asian (SAS)

AF:

0.0000126

AC:

AN:

79158

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48854

Middle Eastern (MID)

AF:

0.000351

AC:

AN:

5696

European-Non Finnish (NFE)

AF:

0.000119

AC:

128

AN:

1078330

Other (OTH)

AF:

0.000173

AC:

AN:

57956

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

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

AF:

0.000545

AC:

AN:

152236

Hom.:

Cov.:

AF XY:

0.000524

AC XY:

AN XY:

74442

show subpopulations

African (AFR)

AF:

0.00169

AC:

AN:

41540

American (AMR)

AF:

0.000392

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.000193

AC:

AN:

5170

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

68002

Other (OTH)

AF:

0.000948

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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

Alfa

AF:

0.000218

Hom.:

Bravo

AF:

0.000620

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.000219

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 13, 2021

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.377C>T (p.P126L) alteration is located in exon 1 (coding exon 1) of the FGD5 gene. This alteration results from a C to T substitution at nucleotide position 377, causing the proline (P) at amino acid position 126 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.51

CADD

Benign

8.7

(source)

DANN

Benign

0.43

DEOGEN2

Benign

0.0027

.;T

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.21

LIST_S2

Benign

0.50

T;T

M_CAP

Benign

0.020

MetaRNN

Benign

0.011

T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

1.5

.;L

PhyloP100

0.43

PrimateAI

Benign

0.33

PROVEAN

Benign

-0.64

.;N

REVEL

Benign

0.088

Sift

Benign

1.0

.;T

Sift4G

Benign

0.15

.;T

Polyphen

0.0

.;B

Vest4

0.10

MVP

0.30

MPC

0.16

ClinPred

0.031

GERP RS

1.7

PromoterAI

0.0026

Neutral

(source)

Varity_R

0.023

gMVP

0.038

Mutation Taster

=94/6

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over