chr4-125449492-G-A

Variant names:

Variant summary

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

The NM_001291303.3(FAT4):c.8482G>A(p.Asp2828Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0141 in 1,613,770 control chromosomes in the GnomAD database, including 1,577 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.028 ( 232 hom., cov: 32)

Exomes 𝑓: 0.013 ( 1345 hom. )

Consequence

FAT4
NM_001291303.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 9.71

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=0.003456831).

BP6

Variant 4-125449492-G-A is Benign according to our data. Variant chr4-125449492-G-A is described in ClinVar as [Benign]. Clinvar id is 380933.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-125449492-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.134 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAT4	NM_001291303.3 link	c.8482G>A	p.Asp2828Asn	missense_variant	Exon 10 of 18	ENST00000394329.9	NP_001278232.1	Q6V0I7A0A6Q8JR05X2G5I7B3KU84

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
FAT4	ENST00000394329.9 link	c.8482G>A	p.Asp2828Asn	missense_variant	Exon 10 of 18	5	NM_001291303.3	ENSP00000377862.4	A0A6Q8JR05
FAT4	ENST00000335110.5 link	c.3370G>A	p.Asp1124Asn	missense_variant	Exon 9 of 15	1		ENSP00000335169.5	Q6V0I7-2
FAT4	ENST00000674496.2 link	c.3253G>A	p.Asp1085Asn	missense_variant	Exon 9 of 17			ENSP00000501473.2	A0A7P0T1I0

Frequencies

GnomAD3 genomes

AF:

0.0280

AC:

4257

AN:

152008

Hom.:

233

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0322

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.128

Gnomad ASJ

AF:

0.000289

Gnomad EAS

AF:

0.143

Gnomad SAS

AF:

0.0315

Gnomad FIN

AF:

0.000189

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.000471

Gnomad OTH

AF:

0.0258

GnomAD3 exomes

AF:

0.0428

AC:

10698

AN:

249844

Hom.:

906

AF XY:

0.0357

AC XY:

4832

AN XY:

135400

show subpopulations

Gnomad AFR exome

AF:

0.0339

Gnomad AMR exome

AF:

0.184

Gnomad ASJ exome

AF:

0.000498

Gnomad EAS exome

AF:

0.150

Gnomad SAS exome

AF:

0.0268

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.000389

Gnomad OTH exome

AF:

0.0284

GnomAD4 exome

AF:

0.0126

AC:

18437

AN:

1461644

Hom.:

1345

Cov.:

AF XY:

0.0121

AC XY:

8801

AN XY:

727112

show subpopulations

Gnomad4 AFR exome

AF:

0.0307

Gnomad4 AMR exome

AF:

0.176

Gnomad4 ASJ exome

AF:

0.000421

Gnomad4 EAS exome

AF:

0.146

Gnomad4 SAS exome

AF:

0.0250

Gnomad4 FIN exome

AF:

0.000150

Gnomad4 NFE exome

AF:

0.000297

Gnomad4 OTH exome

AF:

0.0202

GnomAD4 genome

AF:

0.0280

AC:

4260

AN:

152126

Hom.:

232

Cov.:

AF XY:

0.0305

AC XY:

2270

AN XY:

74366

show subpopulations

Gnomad4 AFR

AF:

0.0322

Gnomad4 AMR

AF:

0.128

Gnomad4 ASJ

AF:

0.000289

Gnomad4 EAS

AF:

0.142

Gnomad4 SAS

AF:

0.0311

Gnomad4 FIN

AF:

0.000189

Gnomad4 NFE

AF:

0.000471

Gnomad4 OTH

AF:

0.0270

Alfa

AF:

0.0117

Hom.:

159

Bravo

AF:

0.0383

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.0302

AC:

133

ESP6500EA

AF:

0.00140

AC:

ExAC

AF:

0.0360

AC:

4364

EpiCase

AF:

0.000600

EpiControl

AF:

0.000237

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Jan 24, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 22% of patients studied by a panel of primary immunodeficiencies. Number of patients: 21. Only high quality variants are reported. -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 21, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.68

BayesDel_noAF

Benign

-0.61

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.028

T;.

Eigen

Uncertain

0.59

Eigen_PC

Pathogenic

0.67

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.94

D;D

MetaRNN

Benign

0.0035

T;T

MetaSVM

Benign

-0.36

MutationAssessor

Benign

-0.23

N;.

PrimateAI

Uncertain

0.58

PROVEAN

Benign

1.5

N;N

REVEL

Benign

0.22

Sift

Benign

1.0

T;T

Sift4G

Uncertain

0.0070

D;D

Polyphen

0.99

D;D

Vest4

0.49

MPC

0.30

ClinPred

0.045

GERP RS

5.6

Varity_R

0.080

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