rs76491994

Positions:

Variant summary

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

The NM_001291303.3(FAT4):c.10810A>C(p.Ile3604Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0138 in 1,614,138 control chromosomes in the GnomAD database, including 221 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.010 ( 16 hom., cov: 32)

Exomes 𝑓: 0.014 ( 205 hom. )

Consequence

FAT4
NM_001291303.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 2.97

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0034600794).

BP6

Variant 4-125451820-A-C is Benign according to our data. Variant chr4-125451820-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 377311.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-125451820-A-C is described in Lovd as [Benign]. Variant chr4-125451820-A-C is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00999 (1522/152288) while in subpopulation EAS AF= 0.0276 (143/5178). AF 95% confidence interval is 0.0239. There are 16 homozygotes in gnomad4. There are 745 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 16 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FAT4	NM_001291303.3 linkuse as main transcript	c.10810A>C	p.Ile3604Leu	missense_variant	10/18	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.10810A>C	p.Ile3604Leu	missense_variant	10/18	5	NM_001291303.3	ENSP00000377862	P1
FAT4	ENST00000335110.5 linkuse as main transcript	c.5698A>C	p.Ile1900Leu	missense_variant	9/15	1		ENSP00000335169		Q6V0I7-2
FAT4	ENST00000674496.2 linkuse as main transcript	c.5581A>C	p.Ile1861Leu	missense_variant	9/17			ENSP00000501473

Frequencies

GnomAD3 genomes

AF:

0.00998

AC:

1519

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00258

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00982

Gnomad ASJ

AF:

0.00230

Gnomad EAS

AF:

0.0279

Gnomad SAS

AF:

0.00705

Gnomad FIN

AF:

0.0154

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0132

Gnomad OTH

AF:

0.00765

GnomAD3 exomes

AF:

0.0120

AC:

3013

AN:

250644

Hom.:

AF XY:

0.0119

AC XY:

1610

AN XY:

135396

show subpopulations

Gnomad AFR exome

AF:

0.00240

Gnomad AMR exome

AF:

0.0103

Gnomad ASJ exome

AF:

0.00149

Gnomad EAS exome

AF:

0.0299

Gnomad SAS exome

AF:

0.00581

Gnomad FIN exome

AF:

0.0168

Gnomad NFE exome

AF:

0.0128

Gnomad OTH exome

AF:

0.0108

GnomAD4 exome

AF:

0.0142

AC:

20814

AN:

1461850

Hom.:

205

Cov.:

AF XY:

0.0140

AC XY:

10180

AN XY:

727230

show subpopulations

Gnomad4 AFR exome

AF:

0.00203

Gnomad4 AMR exome

AF:

0.0101

Gnomad4 ASJ exome

AF:

0.00184

Gnomad4 EAS exome

AF:

0.0206

Gnomad4 SAS exome

AF:

0.00657

Gnomad4 FIN exome

AF:

0.0168

Gnomad4 NFE exome

AF:

0.0155

Gnomad4 OTH exome

AF:

0.0112

GnomAD4 genome

AF:

0.00999

AC:

1522

AN:

152288

Hom.:

Cov.:

AF XY:

0.0100

AC XY:

745

AN XY:

74464

show subpopulations

Gnomad4 AFR

AF:

0.00257

Gnomad4 AMR

AF:

0.0101

Gnomad4 ASJ

AF:

0.00230

Gnomad4 EAS

AF:

0.0276

Gnomad4 SAS

AF:

0.00726

Gnomad4 FIN

AF:

0.0154

Gnomad4 NFE

AF:

0.0132

Gnomad4 OTH

AF:

0.00757

Alfa

AF:

0.0131

Hom.:

Bravo

AF:

0.00918

TwinsUK

AF:

0.0183

AC:

ALSPAC

AF:

0.0161

AC:

ESP6500AA

AF:

0.00409

AC:

ESP6500EA

AF:

0.0140

AC:

120

ExAC

AF:

0.0112

AC:

1357

Asia WGS

AF:

0.0120

AC:

AN:

3478

EpiCase

AF:

0.0126

EpiControl

AF:

0.0132

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
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	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 04, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	FAT4: BP4, BS1, BS2 -

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 28, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: 3% of E. Asian chromosomes in ExAC -

Van Maldergem syndrome 2;C4014939:Hennekam lymphangiectasia-lymphedema syndrome 2

Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 25, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.26

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.46

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Benign

0.16

T;.

Eigen

Benign

-0.67

Eigen_PC

Benign

-0.67

FATHMM_MKL

Uncertain

0.86

LIST_S2

Uncertain

0.88

D;D

MetaRNN

Benign

0.0035

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.2

M;.

MutationTaster

Benign

0.98

D;D

PrimateAI

Benign

0.38

PROVEAN

Benign

-1.9

N;N

REVEL

Benign

0.064

Sift

Uncertain

0.010

D;D

Sift4G

Uncertain

0.014

D;D

Polyphen

0.27

B;B

Vest4

0.22

MPC

0.41

ClinPred

0.011

GERP RS

0.80

Varity_R

0.32

gMVP

0.45

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