6-41771220-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_006653.5(FRS3):​c.878G>A​(p.Gly293Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000375 in 1,573,402 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000085 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000032 ( 0 hom. )

Consequence

FRS3
NM_006653.5 missense

Scores

2
17

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.42
Variant links:
Genes affected
FRS3 (HGNC:16970): (fibroblast growth factor receptor substrate 3) This gene encodes a substrate for the fibroblast growth factor receptor. The encoded protein is found in the peripheral plasma membrane and links fibroblast growth factor receptor stimulation to activators of Ras. The encoded protein down-regulates extracellular regulated kinase 2 through direct binding. [provided by RefSeq, Jul 2013]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.012194902).
BS2
High AC in GnomAd4 at 13 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
FRS3NM_006653.5 linkc.878G>A p.Gly293Glu missense_variant Exon 7 of 7 ENST00000373018.7 NP_006644.1 O43559A0A140VJJ7
FRS3XM_011514254.2 linkc.878G>A p.Gly293Glu missense_variant Exon 7 of 7 XP_011512556.1 O43559A0A140VJJ7
FRS3XM_047418097.1 linkc.878G>A p.Gly293Glu missense_variant Exon 8 of 8 XP_047274053.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
FRS3ENST00000373018.7 linkc.878G>A p.Gly293Glu missense_variant Exon 7 of 7 3 NM_006653.5 ENSP00000362109.3 O43559
FRS3ENST00000259748.6 linkc.878G>A p.Gly293Glu missense_variant Exon 6 of 6 1 ENSP00000259748.2 O43559

Frequencies

GnomAD3 genomes
AF:
0.0000855
AC:
13
AN:
152110
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00231
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.000121
AC:
27
AN:
222534
Hom.:
0
AF XY:
0.000118
AC XY:
14
AN XY:
118556
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00138
Gnomad SAS exome
AF:
0.0000420
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.000188
GnomAD4 exome
AF:
0.0000324
AC:
46
AN:
1421174
Hom.:
0
Cov.:
33
AF XY:
0.0000328
AC XY:
23
AN XY:
701252
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00112
Gnomad4 SAS exome
AF:
0.0000126
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.0000171
GnomAD4 genome
AF:
0.0000854
AC:
13
AN:
152228
Hom.:
0
Cov.:
32
AF XY:
0.0000940
AC XY:
7
AN XY:
74438
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00232
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.000473
Alfa
AF:
0.0000298
Hom.:
0
Bravo
AF:
0.0000718
TwinsUK
AF:
0.00
AC:
0
ALSPAC
AF:
0.000259
AC:
1
ExAC
AF:
0.0000990
AC:
12
Asia WGS
AF:
0.000289
AC:
1
AN:
3478

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Dec 05, 2022
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.878G>A (p.G293E) alteration is located in exon 7 (coding exon 5) of the FRS3 gene. This alteration results from a G to A substitution at nucleotide position 878, causing the glycine (G) at amino acid position 293 to be replaced by a glutamic acid (E). 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
0.13
BayesDel_addAF
Benign
-0.45
T
BayesDel_noAF
Benign
-0.42
CADD
Benign
13
DANN
Benign
0.97
DEOGEN2
Benign
0.24
T;T
Eigen
Benign
-0.39
Eigen_PC
Benign
-0.38
FATHMM_MKL
Benign
0.18
N
LIST_S2
Benign
0.71
T;.
M_CAP
Benign
0.011
T
MetaRNN
Benign
0.012
T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
1.6
L;L
PrimateAI
Uncertain
0.56
T
PROVEAN
Benign
-1.4
N;N
REVEL
Benign
0.065
Sift
Uncertain
0.0050
D;D
Sift4G
Benign
0.25
T;T
Polyphen
0.18
B;B
Vest4
0.33
MVP
0.15
MPC
0.31
ClinPred
0.058
T
GERP RS
4.1
Varity_R
0.14
gMVP
0.51

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs200811439; hg19: chr6-41738958; API