Variant 12-69574694-T-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP3BS2

The NM_001278356.2(FRS2):c.1266T>G(p.Phe422Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000161 in 1,614,072 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 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

FRS2
NM_001278356.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.94

Variant links:

Genes affected

FRS2 (HGNC:16971): (fibroblast growth factor receptor substrate 2) Enables fibroblast growth factor receptor binding activity and neurotrophin TRKA receptor binding activity. Involved in negative regulation of cardiac muscle cell differentiation. Acts upstream of or within fibroblast growth factor receptor signaling pathway. Located in adherens junction. Biomarker of renal cell carcinoma. [provided by Alliance of Genome Resources, Apr 2022]

FRS2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.747

BS2

High AC in GnomAdExome4 at 22 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FRS2	NM_001278356.2 linkuse as main transcript	c.1266T>G	p.Phe422Leu	missense_variant	9/9	ENST00000549921.6	NP_001265285.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
FRS2	ENST00000549921.6 linkuse as main transcript	c.1266T>G	p.Phe422Leu	missense_variant	9/9	1	NM_001278356.2	ENSP00000450048	P1
FRS2	ENST00000550389.5 linkuse as main transcript	c.1266T>G	p.Phe422Leu	missense_variant	7/7	1		ENSP00000447241	P1
FRS2	ENST00000397997.6 linkuse as main transcript	c.1266T>G	p.Phe422Leu	missense_variant	7/7	5		ENSP00000381083	P1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

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:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000802

AC:

AN:

249314

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135284

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:

0.00

Gnomad NFE exome

AF:

0.0000177

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000150

AC:

AN:

1461864

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

727234

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000198

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152208

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74364

show subpopulations

Gnomad4 AFR

AF:

0.0000724

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.00000827

AC:

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

May 14, 2024

The c.1266T>G (p.F422L) alteration is located in exon 10 (coding exon 5) of the FRS2 gene. This alteration results from a T to G substitution at nucleotide position 1266, causing the phenylalanine (F) at amino acid position 422 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

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Uncertain

0.050

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.88

D;D;D

Eigen

Uncertain

0.55

Eigen_PC

Uncertain

0.56

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.96

.;.;D

M_CAP

Benign

0.027

MetaRNN

Pathogenic

0.75

D;D;D

MetaSVM

Benign

-0.70

MutationAssessor

Uncertain

2.5

M;M;M

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Pathogenic

0.82

PROVEAN

Uncertain

-2.9

D;D;D

REVEL

Benign

0.27

Sift

Pathogenic

0.0

D;D;D

Sift4G

Uncertain

0.037

D;D;D

Polyphen

0.96

P;P;P

Vest4

0.76

MutPred

0.56

Gain of catalytic residue at F422 (P = 0);Gain of catalytic residue at F422 (P = 0);Gain of catalytic residue at F422 (P = 0);

MVP

0.82

ClinPred

0.97

GERP RS

5.0

Varity_R

0.67

gMVP

0.68

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