Genetic Variant FRS3:p.Arg406Trp (chr6-41770882-G-A) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_006653.5(FRS3):c.1216C>T(p.Arg406Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000162 in 1,609,710 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000015 ( 0 hom. )

Consequence

FRS3
NM_006653.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.97

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 -4 ACMG points.

BS2

High AC in GnomAdExome4 at 22 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FRS3	NM_006653.5 link	c.1216C>T	p.Arg406Trp	missense_variant	Exon 7 of 7	ENST00000373018.7	NP_006644.1	O43559A0A140VJJ7
FRS3	XM_011514254.2 link	c.1216C>T	p.Arg406Trp	missense_variant	Exon 7 of 7		XP_011512556.1	O43559A0A140VJJ7
FRS3	XM_047418097.1 link	c.1216C>T	p.Arg406Trp	missense_variant	Exon 8 of 8		XP_047274053.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FRS3	ENST00000373018.7 link	c.1216C>T	p.Arg406Trp	missense_variant	Exon 7 of 7	3	NM_006653.5	ENSP00000362109.3		O43559
FRS3	ENST00000259748.6 link	c.1216C>T	p.Arg406Trp	missense_variant	Exon 6 of 6	1		ENSP00000259748.2		O43559

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000453

AC:

AN:

243016

Hom.:

AF XY:

0.0000226

AC XY:

AN XY:

132858

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000203

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000551

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000181

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000151

AC:

AN:

1457396

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

725162

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000157

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000108

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152314

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74468

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000653

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000378

ExAC

AF:

0.0000496

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 15, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1216C>T (p.R406W) alteration is located in exon 7 (coding exon 5) of the FRS3 gene. This alteration results from a C to T substitution at nucleotide position 1216, causing the arginine (R) at amino acid position 406 to be replaced by a tryptophan (W). 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

0.18

BayesDel_addAF

Benign

-0.094

BayesDel_noAF

Benign

-0.10

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.56

D;D

Eigen

Uncertain

0.44

Eigen_PC

Uncertain

0.39

FATHMM_MKL

Uncertain

0.95

LIST_S2

Pathogenic

0.97

D;.

M_CAP

Benign

0.041

MetaRNN

Uncertain

0.67

D;D

MetaSVM

Benign

-0.96

MutationAssessor

Uncertain

2.4

M;M

PrimateAI

Pathogenic

0.85

PROVEAN

Uncertain

-3.8

D;D

REVEL

Benign

0.24

Sift

Pathogenic

0.0

D;D

Sift4G

Uncertain

0.0020

D;D

Polyphen

1.0

D;D

Vest4

0.63

MutPred

0.42

Loss of disorder (P = 0.0201);Loss of disorder (P = 0.0201);

MVP

0.37

MPC

0.87

ClinPred

0.79

GERP RS

2.8

Varity_R

0.50

gMVP

0.71

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