4-186588777-C-T

Position:

chr4-186588777-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_005245.4(FAT1):c.13582G>A(p.Glu4528Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00546 in 1,613,982 control chromosomes in the GnomAD database, including 41 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0044 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0056 ( 38 hom. )

Consequence

FAT1
NM_005245.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 7.38

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0047872365).

BP6

Variant 4-186588777-C-T is Benign according to our data. Variant chr4-186588777-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 791620.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-186588777-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00437 (665/152274) while in subpopulation NFE AF= 0.00622 (423/68020). AF 95% confidence interval is 0.00573. There are 3 homozygotes in gnomad4. There are 341 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
FAT1	NM_005245.4 linkuse as main transcript	c.13582G>A	p.Glu4528Lys	missense_variant	27/27	ENST00000441802.7
FAT1	XM_005262834.4 linkuse as main transcript	c.13618G>A	p.Glu4540Lys	missense_variant	28/28
FAT1	XM_005262835.3 linkuse as main transcript	c.13618G>A	p.Glu4540Lys	missense_variant	28/28
FAT1	XM_006714139.4 linkuse as main transcript	c.13582G>A	p.Glu4528Lys	missense_variant	27/27

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
FAT1	ENST00000441802.7 linkuse as main transcript	c.13582G>A	p.Glu4528Lys	missense_variant	27/27	5	NM_005245.4	P1
FAT1	ENST00000512772.5 linkuse as main transcript	c.922G>A	p.Glu308Lys	missense_variant	4/4	2
FAT1	ENST00000500085.2 linkuse as main transcript	n.1274G>A		non_coding_transcript_exon_variant	3/3	2
FAT1	ENST00000507105.1 linkuse as main transcript			downstream_gene_variant		3

Frequencies

GnomAD3 genomes

AF:

0.00437

AC:

665

AN:

152156

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00111

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00144

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.0159

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00622

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.00538

AC:

1341

AN:

249212

Hom.:

AF XY:

0.00539

AC XY:

728

AN XY:

135190

show subpopulations

Gnomad AFR exome

AF:

0.00136

Gnomad AMR exome

AF:

0.00127

Gnomad ASJ exome

AF:

0.0000994

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00111

Gnomad FIN exome

AF:

0.0161

Gnomad NFE exome

AF:

0.00768

Gnomad OTH exome

AF:

0.00430

GnomAD4 exome

AF:

0.00557

AC:

8148

AN:

1461708

Hom.:

Cov.:

AF XY:

0.00542

AC XY:

3944

AN XY:

727134

show subpopulations

Gnomad4 AFR exome

AF:

0.000986

Gnomad4 AMR exome

AF:

0.00125

Gnomad4 ASJ exome

AF:

0.000115

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000962

Gnomad4 FIN exome

AF:

0.0169

Gnomad4 NFE exome

AF:

0.00613

Gnomad4 OTH exome

AF:

0.00421

GnomAD4 genome

AF:

0.00437

AC:

665

AN:

152274

Hom.:

Cov.:

AF XY:

0.00458

AC XY:

341

AN XY:

74448

show subpopulations

Gnomad4 AFR

AF:

0.00111

Gnomad4 AMR

AF:

0.00144

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000415

Gnomad4 FIN

AF:

0.0159

Gnomad4 NFE

AF:

0.00622

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00526

Hom.:

Bravo

AF:

0.00348

TwinsUK

AF:

0.00701

AC:

ALSPAC

AF:

0.00597

AC:

ESP6500AA

AF:

0.00120

AC:

ESP6500EA

AF:

0.00794

AC:

ExAC

AF:

0.00637

AC:

771

EpiCase

AF:

0.00534

EpiControl

AF:

0.00510

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	FAT1: BP4, BS2 -

FAT1-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 01, 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). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.37

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.12

T;T

Eigen

Benign

0.17

Eigen_PC

Benign

0.14

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.88

D;D

MetaRNN

Benign

0.0048

T;T

MetaSVM

Benign

-0.55

MutationAssessor

Uncertain

2.3

M;.

MutationTaster

Benign

1.0

PrimateAI

Benign

0.37

PROVEAN

Benign

-0.99

N;.

REVEL

Benign

0.19

Sift

Benign

0.19

T;.

Sift4G

Uncertain

0.031

D;D

Polyphen

0.78

P;.

Vest4

0.35

MVP

0.42

MPC

0.13

ClinPred

0.038

GERP RS

5.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.12

gMVP

0.22

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