rs1432862

Positions:

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBA1

The ENST00000261800.6(FAT2):c.1720C>T(p.Arg574Cys) variant causes a missense change. The variant allele was found at a frequency of 0.503 in 1,613,572 control chromosomes in the GnomAD database, including 207,845 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R574H) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.48 ( 18000 hom., cov: 32)

Exomes 𝑓: 0.51 ( 189845 hom. )

Consequence

FAT2
ENST00000261800.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 6.76

Variant links:

Genes affected

FAT2 (HGNC:3596): (FAT atypical cadherin 2) This gene is the second identified human homolog of the Drosophila fat gene, which encodes a tumor suppressor essential for controlling cell proliferation during Drosophila development. The gene product is a member of the cadherin superfamily, a group of integral membrane proteins characterized by the presence of cadherin-type repeats. In addition to containing 34 tandem cadherin-type repeats, the gene product has two epidermal growth factor (EGF)-like repeats and one laminin G domain. This protein most likely functions as a cell adhesion molecule, controlling cell proliferation and playing an important role in cerebellum development. [provided by RefSeq, Jul 2008]

FAT2 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), FAT2. . Gene score misZ 0.71686 (greater than the threshold 3.09). Trascript score misZ 4.0451 (greater than threshold 3.09). GenCC has associacion of gene with spinocerebellar ataxia 45.

BP4

Computational evidence support a benign effect (MetaRNN=0.0021697283).

BP6

Variant 5-151567212-G-A is Benign according to our data. Variant chr5-151567212-G-A is described in ClinVar as [Benign]. Clinvar id is 1249058.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.523 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FAT2	NM_001447.3 linkuse as main transcript	c.1720C>T	p.Arg574Cys	missense_variant	2/24	ENST00000261800.6	NP_001438.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FAT2	ENST00000261800.6 linkuse as main transcript	c.1720C>T	p.Arg574Cys	missense_variant	2/24	1	NM_001447.3	ENSP00000261800	P1

Frequencies

GnomAD3 genomes

AF:

0.484

AC:

73489

AN:

151866

Hom.:

17987

Cov.:

show subpopulations

Gnomad AFR

AF:

0.439

Gnomad AMI

AF:

0.354

Gnomad AMR

AF:

0.446

Gnomad ASJ

AF:

0.531

Gnomad EAS

AF:

0.348

Gnomad SAS

AF:

0.361

Gnomad FIN

AF:

0.553

Gnomad MID

AF:

0.497

Gnomad NFE

AF:

0.528

Gnomad OTH

AF:

0.487

GnomAD3 exomes

AF:

0.466

AC:

116880

AN:

251070

Hom.:

28361

AF XY:

0.468

AC XY:

63509

AN XY:

135740

show subpopulations

Gnomad AFR exome

AF:

0.434

Gnomad AMR exome

AF:

0.340

Gnomad ASJ exome

AF:

0.529

Gnomad EAS exome

AF:

0.359

Gnomad SAS exome

AF:

0.357

Gnomad FIN exome

AF:

0.550

Gnomad NFE exome

AF:

0.531

Gnomad OTH exome

AF:

0.507

GnomAD4 exome

AF:

0.505

AC:

738745

AN:

1461588

Hom.:

189845

Cov.:

AF XY:

0.502

AC XY:

364928

AN XY:

727088

show subpopulations

Gnomad4 AFR exome

AF:

0.435

Gnomad4 AMR exome

AF:

0.352

Gnomad4 ASJ exome

AF:

0.535

Gnomad4 EAS exome

AF:

0.324

Gnomad4 SAS exome

AF:

0.362

Gnomad4 FIN exome

AF:

0.546

Gnomad4 NFE exome

AF:

0.529

Gnomad4 OTH exome

AF:

0.506

GnomAD4 genome

AF:

0.484

AC:

73527

AN:

151984

Hom.:

18000

Cov.:

AF XY:

0.481

AC XY:

35715

AN XY:

74286

show subpopulations

Gnomad4 AFR

AF:

0.438

Gnomad4 AMR

AF:

0.445

Gnomad4 ASJ

AF:

0.531

Gnomad4 EAS

AF:

0.348

Gnomad4 SAS

AF:

0.362

Gnomad4 FIN

AF:

0.553

Gnomad4 NFE

AF:

0.528

Gnomad4 OTH

AF:

0.483

Alfa

AF:

0.515

Hom.:

50170

Bravo

AF:

0.475

TwinsUK

AF:

0.518

AC:

1922

ALSPAC

AF:

0.531

AC:

2045

ESP6500AA

AF:

0.439

AC:

1936

ESP6500EA

AF:

0.523

AC:

4501

ExAC

AF:

0.467

AC:

56713

Asia WGS

AF:

0.384

AC:

1335

AN:

3478

EpiCase

AF:

0.526

EpiControl

AF:

0.531

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -

FAT2-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 08, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Spinocerebellar ataxia 45

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.47

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.22

Eigen

Uncertain

0.24

Eigen_PC

Benign

0.13

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.85

MetaRNN

Benign

0.0022

MetaSVM

Benign

-0.92

MutationAssessor

Uncertain

2.5

MutationTaster

Benign

0.0081

PrimateAI

Benign

0.19

PROVEAN

Benign

-1.4

REVEL

Benign

0.28

Sift

Uncertain

0.017

Sift4G

Uncertain

0.0080

Polyphen

0.99

Vest4

0.094

MPC

0.52

ClinPred

0.033

GERP RS

4.3

Varity_R

0.33

gMVP

0.53

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