rs35340865

Positions:

chr4-125491479-C-G

Variant summary

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

The NM_001291303.3(FAT4):c.14663C>G(p.Ala4888Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00146 in 1,614,118 control chromosomes in the GnomAD database, including 17 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 0.0052 ( 8 hom., cov: 33)

Exomes 𝑓: 0.0011 ( 9 hom. )

Consequence

FAT4
NM_001291303.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 3.39

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=0.007138908).

BP6

Variant 4-125491479-C-G is Benign according to our data. Variant chr4-125491479-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 445551.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-125491479-C-G is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00516 (785/152238) while in subpopulation AFR AF= 0.0157 (651/41530). AF 95% confidence interval is 0.0147. There are 8 homozygotes in gnomad4. There are 372 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FAT4	NM_001291303.3 linkuse as main transcript	c.14663C>G	p.Ala4888Gly	missense_variant	18/18	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.14663C>G	p.Ala4888Gly	missense_variant	18/18	5	NM_001291303.3	ENSP00000377862	P1
FAT4	ENST00000335110.5 linkuse as main transcript	c.9380C>G	p.Ala3127Gly	missense_variant	15/15	1		ENSP00000335169		Q6V0I7-2
FAT4	ENST00000674496.2 linkuse as main transcript	c.9434C>G	p.Ala3145Gly	missense_variant	17/17			ENSP00000501473

Frequencies

GnomAD3 genomes

AF:

0.00515

AC:

784

AN:

152120

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0157

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00406

Gnomad ASJ

AF:

0.00634

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000470

Gnomad OTH

AF:

0.00765

GnomAD3 exomes

AF:

0.00203

AC:

511

AN:

251330

Hom.:

AF XY:

0.00179

AC XY:

243

AN XY:

135848

show subpopulations

Gnomad AFR exome

AF:

0.0158

Gnomad AMR exome

AF:

0.00191

Gnomad ASJ exome

AF:

0.00953

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000634

Gnomad OTH exome

AF:

0.00310

GnomAD4 exome

AF:

0.00107

AC:

1569

AN:

1461880

Hom.:

Cov.:

AF XY:

0.00103

AC XY:

751

AN XY:

727238

show subpopulations

Gnomad4 AFR exome

AF:

0.0159

Gnomad4 AMR exome

AF:

0.00215

Gnomad4 ASJ exome

AF:

0.00792

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000474

Gnomad4 OTH exome

AF:

0.00305

GnomAD4 genome

AF:

0.00516

AC:

785

AN:

152238

Hom.:

Cov.:

AF XY:

0.00500

AC XY:

372

AN XY:

74442

show subpopulations

Gnomad4 AFR

AF:

0.0157

Gnomad4 AMR

AF:

0.00405

Gnomad4 ASJ

AF:

0.00634

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000470

Gnomad4 OTH

AF:

0.00757

Alfa

AF:

0.00211

Hom.:

Bravo

AF:

0.00608

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.0152

AC:

ESP6500EA

AF:

0.000930

AC:

ExAC

AF:

0.00232

AC:

282

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.000763

EpiControl

AF:

0.00113

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 06, 2018	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. -

not provided

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	May 04, 2017	- -
Likely 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	- -

FAT4-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 14, 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

0.075

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.50

CADD

Benign

DANN

Benign

0.92

DEOGEN2

Benign

0.039

T;.

Eigen

Benign

-0.27

Eigen_PC

Benign

-0.089

FATHMM_MKL

Uncertain

0.84

LIST_S2

Benign

0.83

T;T

MetaRNN

Benign

0.0071

T;T

MetaSVM

Benign

-0.85

MutationAssessor

Benign

1.1

L;.

MutationTaster

Benign

0.86

N;N

PrimateAI

Uncertain

0.48

PROVEAN

Benign

-0.45

N;N

REVEL

Benign

0.18

Sift

Benign

0.21

T;T

Sift4G

Benign

0.68

T;T

Polyphen

0.0

B;B

Vest4

0.067

MVP

0.14

MPC

0.15

ClinPred

0.011

GERP RS

5.2

Varity_R

0.085

gMVP

0.18

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