4-125414950-A-G

Position:

chr4-125414950-A-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001291303.3(FAT4):c.5987A>G(p.Lys1996Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00113 in 1,613,814 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0024 ( 4 hom., cov: 32)

Exomes 𝑓: 0.0010 ( 6 hom. )

Consequence

FAT4
NM_001291303.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:7

Conservation

PhyloP100: 1.35

Variant links:

Genes affected

FAT4 (HGNC:23109): (FAT atypical cadherin 4) The protein encoded by this gene is a member of the protocadherin family. This gene may play a role in regulating planar cell polarity (PCP). Studies in mice suggest that loss of PCP signaling may cause cystic kidney disease, and mutations in this gene have been associated with Van Maldergem Syndrome 2. Alternatively spliced transcript variants have been noted for this gene. [provided by RefSeq, Mar 2014]

FAT4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0068081915).

BP6

Variant 4-125414950-A-G is Benign according to our data. Variant chr4-125414950-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 435175.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=1}. Variant chr4-125414950-A-G is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00239 (364/152254) while in subpopulation AMR AF= 0.00805 (123/15286). AF 95% confidence interval is 0.00689. There are 4 homozygotes in gnomad4. There are 181 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FAT4	NM_001291303.3 linkuse as main transcript	c.5987A>G	p.Lys1996Arg	missense_variant	6/18	ENST00000394329.9	NP_001278232.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FAT4	ENST00000394329.9 linkuse as main transcript	c.5987A>G	p.Lys1996Arg	missense_variant	6/18	5	NM_001291303.3	ENSP00000377862	P1
FAT4	ENST00000335110.5 linkuse as main transcript	c.881A>G	p.Lys294Arg	missense_variant	5/15	1		ENSP00000335169		Q6V0I7-2
FAT4	ENST00000674496.2 linkuse as main transcript	c.758A>G	p.Lys253Arg	missense_variant	5/17			ENSP00000501473

Frequencies

GnomAD3 genomes

AF:

0.00239

AC:

364

AN:

152136

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00340

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00806

Gnomad ASJ

AF:

0.000867

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00118

Gnomad OTH

AF:

0.00669

GnomAD3 exomes

AF:

0.00146

AC:

366

AN:

251014

Hom.:

AF XY:

0.00125

AC XY:

170

AN XY:

135632

show subpopulations

Gnomad AFR exome

AF:

0.00357

Gnomad AMR exome

AF:

0.00382

Gnomad ASJ exome

AF:

0.00209

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000980

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00116

Gnomad OTH exome

AF:

0.00343

GnomAD4 exome

AF:

0.00100

AC:

1465

AN:

1461560

Hom.:

Cov.:

AF XY:

0.000967

AC XY:

703

AN XY:

727044

show subpopulations

Gnomad4 AFR exome

AF:

0.00320

Gnomad4 AMR exome

AF:

0.00387

Gnomad4 ASJ exome

AF:

0.00145

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000812

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000871

Gnomad4 OTH exome

AF:

0.00227

GnomAD4 genome

AF:

0.00239

AC:

364

AN:

152254

Hom.:

Cov.:

AF XY:

0.00243

AC XY:

181

AN XY:

74442

show subpopulations

Gnomad4 AFR

AF:

0.00339

Gnomad4 AMR

AF:

0.00805

Gnomad4 ASJ

AF:

0.000867

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00118

Gnomad4 OTH

AF:

0.00662

Alfa

AF:

0.00105

Hom.:

Bravo

AF:

0.00300

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.00386

AC:

ESP6500EA

AF:

0.000930

AC:

ExAC

AF:

0.00118

AC:

143

EpiCase

AF:

0.00169

EpiControl

AF:

0.00166

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:7

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:5

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	FAT4: BP4, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 26, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 23, 2021	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Sep 14, 2016

- -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 25, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

FAT4-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 09, 2020

This variant is classified as likely 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

0.068

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.65

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.071

T;.

Eigen

Benign

-0.72

Eigen_PC

Benign

-0.68

FATHMM_MKL

Uncertain

0.83

LIST_S2

Benign

0.54

T;T

M_CAP

Benign

0.0076

MetaRNN

Benign

0.0068

T;T

MetaSVM

Benign

-0.90

MutationAssessor

Benign

0.14

N;.

MutationTaster

Benign

0.57

N;N

PrimateAI

Benign

0.29

PROVEAN

Benign

-1.1

N;N

REVEL

Benign

0.064

Sift

Benign

0.29

T;T

Sift4G

Uncertain

0.034

D;D

Polyphen

0.93

P;B

Vest4

0.053

MVP

0.19

MPC

0.17

ClinPred

0.0087

GERP RS

2.9

Varity_R

0.023

gMVP

0.21

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