chr3-14819298-A-T

Position:

• chr3-14819298-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000543601(FGD5):​c.-497A>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: FGD5 ENST00000543601 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.637

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09489006).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FGD5	NM_152536.4	c.227A>T	p.Asp76Val	missense_variant	1/20	ENST00000285046.10	NP_689749.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FGD5	ENST00000543601	c.-497A>T		5_prime_UTR_premature_start_codon_gain_variant	1/19	1		ENSP00000445949.1
FGD5	ENST00000285046.10	c.227A>T	p.Asp76Val	missense_variant	1/20	1	NM_152536.4	ENSP00000285046.5
FGD5	ENST00000543601	c.-497A>T		5_prime_UTR_variant	1/19	1		ENSP00000445949.1
FGD5	ENST00000640506.1	c.356A>T	p.Asp119Val	missense_variant	2/2	5		ENSP00000492654.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 18, 2022

The c.227A>T (p.D76V) alteration is located in exon 1 (coding exon 1) of the FGD5 gene. This alteration results from a A to T substitution at nucleotide position 227, causing the aspartic acid (D) at amino acid position 76 to be replaced by a valine (V). 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	0.11
BayesDel_addAF	Benign	-0.042	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	5.2
DANN	Benign	0.97
DEOGEN2	Benign	0.0061	.;T
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.85
FATHMM_MKL	Benign	0.63	D
LIST_S2	Benign	0.58	T;T
M_CAP	Benign	0.071	D
MetaRNN	Benign	0.095	T;T
MetaSVM	Benign	-0.83	T
MutationAssessor	Uncertain	2.0	.;M
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-2.3	.;N
REVEL	Benign	0.14
Sift	Uncertain	0.0020	.;D
Sift4G	Uncertain	0.053	.;T
Polyphen		0.039	.;B
Vest4		0.15
MutPred		0.23		.;Gain of sheet (P = 0.0073);
MVP		0.58
MPC		0.23
ClinPred		0.16	T
GERP RS		-0.98
Varity_R		0.11
gMVP		0.14

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-14860805;