chr4-125451587-G-A

Position:

chr4-125451587-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001291303.3(FAT4):c.10577G>A(p.Gly3526Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.279 in 1,613,874 control chromosomes in the GnomAD database, including 65,712 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.22 ( 4646 hom., cov: 32)

Exomes 𝑓: 0.29 ( 61066 hom. )

Consequence

FAT4
NM_001291303.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 9.80

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=0.0034423769).

BP6

Variant 4-125451587-G-A is Benign according to our data. Variant chr4-125451587-G-A is described in ClinVar as [Benign]. Clinvar id is 380813.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-125451587-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.393 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FAT4	NM_001291303.3 linkuse as main transcript	c.10577G>A	p.Gly3526Asp	missense_variant	10/18	ENST00000394329.9	NP_001278232.1	Q6V0I7A0A6Q8JR05X2G5I7B3KU84

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
FAT4	ENST00000394329.9 linkuse as main transcript	c.10577G>A	p.Gly3526Asp	missense_variant	10/18	5	NM_001291303.3	ENSP00000377862.4	A0A6Q8JR05
FAT4	ENST00000335110.5 linkuse as main transcript	c.5465G>A	p.Gly1822Asp	missense_variant	9/15	1		ENSP00000335169.5	Q6V0I7-2
FAT4	ENST00000674496.2 linkuse as main transcript	c.5348G>A	p.Gly1783Asp	missense_variant	9/17			ENSP00000501473.2	A0A7P0T1I0

Frequencies

GnomAD3 genomes

AF:

0.224

AC:

34068

AN:

151900

Hom.:

4637

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0641

Gnomad AMI

AF:

0.403

Gnomad AMR

AF:

0.246

Gnomad ASJ

AF:

0.281

Gnomad EAS

AF:

0.407

Gnomad SAS

AF:

0.279

Gnomad FIN

AF:

0.241

Gnomad MID

AF:

0.177

Gnomad NFE

AF:

0.291

Gnomad OTH

AF:

0.248

GnomAD3 exomes

AF:

0.272

AC:

68286

AN:

251236

Hom.:

9963

AF XY:

0.277

AC XY:

37584

AN XY:

135794

show subpopulations

Gnomad AFR exome

AF:

0.0591

Gnomad AMR exome

AF:

0.246

Gnomad ASJ exome

AF:

0.270

Gnomad EAS exome

AF:

0.420

Gnomad SAS exome

AF:

0.293

Gnomad FIN exome

AF:

0.242

Gnomad NFE exome

AF:

0.286

Gnomad OTH exome

AF:

0.270

GnomAD4 exome

AF:

0.285

AC:

416655

AN:

1461854

Hom.:

61066

Cov.:

AF XY:

0.286

AC XY:

207893

AN XY:

727230

show subpopulations

Gnomad4 AFR exome

AF:

0.0556

Gnomad4 AMR exome

AF:

0.244

Gnomad4 ASJ exome

AF:

0.273

Gnomad4 EAS exome

AF:

0.411

Gnomad4 SAS exome

AF:

0.291

Gnomad4 FIN exome

AF:

0.239

Gnomad4 NFE exome

AF:

0.292

Gnomad4 OTH exome

AF:

0.275

GnomAD4 genome

AF:

0.224

AC:

34099

AN:

152020

Hom.:

4646

Cov.:

AF XY:

0.223

AC XY:

16603

AN XY:

74296

show subpopulations

Gnomad4 AFR

AF:

0.0640

Gnomad4 AMR

AF:

0.247

Gnomad4 ASJ

AF:

0.281

Gnomad4 EAS

AF:

0.407

Gnomad4 SAS

AF:

0.279

Gnomad4 FIN

AF:

0.241

Gnomad4 NFE

AF:

0.291

Gnomad4 OTH

AF:

0.252

Alfa

AF:

0.282

Hom.:

15486

Bravo

AF:

0.220

TwinsUK

AF:

0.297

AC:

1101

ALSPAC

AF:

0.302

AC:

1163

ESP6500AA

AF:

0.0663

AC:

292

ESP6500EA

AF:

0.300

AC:

2578

ExAC

AF:

0.267

AC:

32446

Asia WGS

AF:

0.314

AC:

1092

AN:

3478

EpiCase

AF:

0.291

EpiControl

AF:

0.290

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
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: 27% of total chromosomes in ExAC -
Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jan 24, 2024	This variant is classified as Benign based on local population frequency. This variant was detected in 46% of patients studied by a panel of primary immunodeficiencies. Number of patients: 44. Only high quality variants are reported. -
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	Jan 27, 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. -

Van Maldergem syndrome 2

Benign:2

Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Hennekam lymphangiectasia-lymphedema syndrome 2

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.26

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.23

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.39

T;.

Eigen

Pathogenic

0.89

Eigen_PC

Pathogenic

0.86

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.91

D;D

MetaRNN

Benign

0.0034

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.8

M;.

PrimateAI

Uncertain

0.67

PROVEAN

Pathogenic

-4.6

D;D

REVEL

Uncertain

0.50

Sift

Uncertain

0.013

D;D

Sift4G

Uncertain

0.0050

D;D

Polyphen

1.0

D;D

Vest4

0.88

MPC

0.74

ClinPred

0.026

GERP RS

5.8

Varity_R

0.41

gMVP

0.72

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