4-186628751-C-T

Position:

chr4-186628751-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2BP4_StrongBP6BS1

The NM_005245.4(FAT1):c.4336G>A(p.Val1446Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00012 in 1,612,744 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00073 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000057 ( 0 hom. )

Consequence

FAT1
NM_005245.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 7.91

Variant links:

Genes affected

FAT1 (HGNC:3595): (FAT atypical cadherin 1) This gene is an ortholog 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 five epidermal growth factor (EGF)-like repeats and one laminin A-G domain. This gene is expressed at high levels in a number of fetal epithelia. Its product probably functions as an adhesion molecule and/or signaling receptor, and is likely to be important in developmental processes and cell communication. Transcript variants derived from alternative splicing and/or alternative promoter usage exist, but they have not been fully described. [provided by RefSeq, Jul 2008]

FAT1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.024121523).

BP6

Variant 4-186628751-C-T is Benign according to our data. Variant chr4-186628751-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 221920.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000729 (111/152284) while in subpopulation AFR AF= 0.00253 (105/41550). AF 95% confidence interval is 0.00214. There are 0 homozygotes in gnomad4. There are 53 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FAT1	NM_005245.4 linkuse as main transcript	c.4336G>A	p.Val1446Ile	missense_variant	8/27	ENST00000441802.7	NP_005236.2	Q14517
FAT1	XM_005262834.4 linkuse as main transcript	c.4336G>A	p.Val1446Ile	missense_variant	8/28		XP_005262891.1
FAT1	XM_005262835.3 linkuse as main transcript	c.4336G>A	p.Val1446Ile	missense_variant	8/28		XP_005262892.1
FAT1	XM_006714139.4 linkuse as main transcript	c.4336G>A	p.Val1446Ile	missense_variant	8/27		XP_006714202.1	Q14517

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FAT1	ENST00000441802.7 linkuse as main transcript	c.4336G>A	p.Val1446Ile	missense_variant	8/27	5	NM_005245.4	ENSP00000406229.2		Q14517

Frequencies

GnomAD3 genomes

AF:

0.000729

AC:

111

AN:

152166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00253

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

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:

0.000478

GnomAD3 exomes

AF:

0.000110

AC:

AN:

246274

Hom.:

AF XY:

0.0000972

AC XY:

AN XY:

133690

show subpopulations

Gnomad AFR exome

AF:

0.00164

Gnomad AMR exome

AF:

0.0000291

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:

0.00

Gnomad OTH exome

AF:

0.000167

GnomAD4 exome

AF:

0.0000568

AC:

AN:

1460460

Hom.:

Cov.:

AF XY:

0.0000523

AC XY:

AN XY:

726536

show subpopulations

Gnomad4 AFR exome

AF:

0.00200

Gnomad4 AMR exome

AF:

0.0000671

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:

9.00e-7

Gnomad4 OTH exome

AF:

0.000182

GnomAD4 genome

AF:

0.000729

AC:

111

AN:

152284

Hom.:

Cov.:

AF XY:

0.000712

AC XY:

AN XY:

74460

show subpopulations

Gnomad4 AFR

AF:

0.00253

Gnomad4 AMR

AF:

0.000261

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:

0.000473

Alfa

AF:

0.000162

Hom.:

Bravo

AF:

0.000706

ESP6500AA

AF:

0.00218

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000232

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 17, 2022

This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 1446 of the FAT1 protein (p.Val1446Ile). This variant is present in population databases (rs200828005, gnomAD 0.2%). This missense change has been observed in individual(s) with microphthalmia and other ocular anomalies (PMID: 26893459). ClinVar contains an entry for this variant (Variation ID: 221920). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt FAT1 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Irido-corneo-trabecular dysgenesis;C5680330:Anophthalmia-microphthalmia syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Paul Sabatier University EA-4555, Paul Sabatier University

Jan 01, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.15

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.16

T;T

Eigen

Pathogenic

0.68

Eigen_PC

Pathogenic

0.71

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.89

D;D

M_CAP

Benign

0.021

MetaRNN

Benign

0.024

T;T

MetaSVM

Benign

-0.36

MutationAssessor

Benign

2.0

M;.

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-0.75

N;.

REVEL

Uncertain

0.32

Sift

Benign

0.10

T;.

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;.

Vest4

0.65

MVP

0.58

MPC

0.41

ClinPred

0.077

GERP RS

5.5

Varity_R

0.11

gMVP

0.29

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