Variant 6-41771283-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_006653.5(FRS3):c.815A>G(p.Asn272Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000175 in 1,612,562 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 0.00013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00018 ( 0 hom. )

Consequence

FRS3
NM_006653.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.80

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]

FRS3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.12258917).

BS2

High AC in GnomAd4 at 20 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FRS3	NM_006653.5 link	c.815A>G	p.Asn272Ser	missense_variant	7/7	ENST00000373018.7	NP_006644.1	O43559A0A140VJJ7
FRS3	XM_011514254.2 link	c.815A>G	p.Asn272Ser	missense_variant	7/7		XP_011512556.1	O43559A0A140VJJ7
FRS3	XM_047418097.1 link	c.815A>G	p.Asn272Ser	missense_variant	8/8		XP_047274053.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FRS3	ENST00000373018.7 link	c.815A>G	p.Asn272Ser	missense_variant	7/7	3	NM_006653.5	ENSP00000362109.3		O43559
FRS3	ENST00000259748.6 link	c.815A>G	p.Asn272Ser	missense_variant	6/6	1		ENSP00000259748.2		O43559

Frequencies

GnomAD3 genomes

AF:

0.000132

AC:

AN:

152016

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000945

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000250

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000148

AC:

AN:

250460

Hom.:

AF XY:

0.000126

AC XY:

AN XY:

135334

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000928

Gnomad NFE exome

AF:

0.000283

Gnomad OTH exome

AF:

0.000493

GnomAD4 exome

AF:

0.000179

AC:

262

AN:

1460428

Hom.:

Cov.:

AF XY:

0.000158

AC XY:

115

AN XY:

726286

show subpopulations

Gnomad4 AFR exome

AF:

0.0000598

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000375

Gnomad4 NFE exome

AF:

0.000220

Gnomad4 OTH exome

AF:

0.000216

GnomAD4 genome

AF:

0.000131

AC:

AN:

152134

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

74392

show subpopulations

Gnomad4 AFR

AF:

0.0000482

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000945

Gnomad4 NFE

AF:

0.000250

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000201

Hom.:

Bravo

AF:

0.000106

ExAC

AF:

0.000206

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000164

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 17, 2023

The c.815A>G (p.N272S) alteration is located in exon 7 (coding exon 5) of the FRS3 gene. This alteration results from a A to G substitution at nucleotide position 815, causing the asparagine (N) at amino acid position 272 to be replaced by a serine (S). 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

-0.43

BayesDel_noAF

Benign

-0.55

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.22

T;T

Eigen

Benign

-0.064

Eigen_PC

Benign

0.12

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.77

T;.

M_CAP

Benign

0.0021

MetaRNN

Benign

0.12

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.6

L;L

PrimateAI

Benign

0.41

PROVEAN

Benign

-0.87

N;N

REVEL

Benign

0.017

Sift

Uncertain

0.012

D;D

Sift4G

Benign

0.37

T;T

Polyphen

0.075

B;B

Vest4

0.31

MutPred

0.21

Gain of glycosylation at N272 (P = 0.0103);Gain of glycosylation at N272 (P = 0.0103);

MVP

0.40

MPC

0.56

ClinPred

0.054

GERP RS

6.0

Varity_R

0.13

gMVP

0.18

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

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over