chr4-125317769-A-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001291303.3(FAT4):c.1358A>T(p.Gln453Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.438 in 1,613,882 control chromosomes in the GnomAD database, including 157,747 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q453R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.46 ( 16452 hom., cov: 32)

Exomes 𝑓: 0.44 ( 141295 hom. )

Consequence

FAT4
NM_001291303.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 0.151

Publications

33 publications found

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 Gene-Disease associations (from GenCC):

Hennekam lymphangiectasia-lymphedema syndrome 2
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
van Maldergem syndrome 2
Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
multiple congenital anomalies/dysmorphic syndrome-intellectual disability
Inheritance: AR Classification: STRONG Submitted by: Ambry Genetics
Hennekam syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
van Maldergem syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

FAT4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=2.3591885E-5).

BP6

Variant 4-125317769-A-T is Benign according to our data. Variant chr4-125317769-A-T is described in ClinVar as Benign. ClinVar VariationId is 380812.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.56 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAT4	NM_001291303.3 link	c.1358A>T	p.Gln453Leu	missense_variant	Exon 2 of 18	ENST00000394329.9	NP_001278232.1	Q6V0I7A0A6Q8JR05X2G5I7B3KU84

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FAT4	ENST00000394329.9 link	c.1358A>T	p.Gln453Leu	missense_variant	Exon 2 of 18	5	NM_001291303.3	ENSP00000377862.4		A0A6Q8JR05
FAT4	ENST00000674496.2 link	c.-55+1792A>T		intron_variant	Intron 1 of 16			ENSP00000501473.2		A0A7P0T1I0

Frequencies

GnomAD3 genomes

AF:

0.459

AC:

69802

AN:

151946

Hom.:

16426

Cov.:

show subpopulations

Gnomad AFR

AF:

0.566

Gnomad AMI

AF:

0.467

Gnomad AMR

AF:

0.403

Gnomad ASJ

AF:

0.353

Gnomad EAS

AF:

0.254

Gnomad SAS

AF:

0.385

Gnomad FIN

AF:

0.390

Gnomad MID

AF:

0.326

Gnomad NFE

AF:

0.445

Gnomad OTH

AF:

0.439

GnomAD2 exomes

AF:

0.414

AC:

103306

AN:

249260

AF XY:

0.413

show subpopulations

Gnomad AFR exome

AF:

0.573

Gnomad AMR exome

AF:

0.377

Gnomad ASJ exome

AF:

0.365

Gnomad EAS exome

AF:

0.245

Gnomad FIN exome

AF:

0.384

Gnomad NFE exome

AF:

0.444

Gnomad OTH exome

AF:

0.411

GnomAD4 exome

AF:

0.436

AC:

637658

AN:

1461818

Hom.:

141295

Cov.:

AF XY:

0.434

AC XY:

315813

AN XY:

727204

show subpopulations

African (AFR)

AF:

0.576

AC:

19287

AN:

33480

American (AMR)

AF:

0.381

AC:

17037

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.364

AC:

9508

AN:

26136

East Asian (EAS)

AF:

0.255

AC:

10110

AN:

39700

South Asian (SAS)

AF:

0.406

AC:

35007

AN:

86254

European-Finnish (FIN)

AF:

0.390

AC:

20788

AN:

53370

Middle Eastern (MID)

AF:

0.354

AC:

2042

AN:

5768

European-Non Finnish (NFE)

AF:

0.448

AC:

498544

AN:

1111994

Other (OTH)

AF:

0.419

AC:

25335

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

24145

48291

72436

96582

120727

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

15020

30040

45060

60080

75100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.460

AC:

69882

AN:

152064

Hom.:

16452

Cov.:

AF XY:

0.454

AC XY:

33731

AN XY:

74318

show subpopulations

African (AFR)

AF:

0.567

AC:

23519

AN:

41512

American (AMR)

AF:

0.402

AC:

6154

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.353

AC:

1223

AN:

3468

East Asian (EAS)

AF:

0.254

AC:

1306

AN:

5138

South Asian (SAS)

AF:

0.386

AC:

1853

AN:

4806

European-Finnish (FIN)

AF:

0.390

AC:

4131

AN:

10584

Middle Eastern (MID)

AF:

0.340

AC:

100

AN:

294

European-Non Finnish (NFE)

AF:

0.445

AC:

30254

AN:

67950

Other (OTH)

AF:

0.434

AC:

919

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1929

3859

5788

7718

9647

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

626

1252

1878

2504

3130

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.400

Hom.:

3650

Bravo

AF:

0.464

TwinsUK

AF:

0.462

AC:

1714

ALSPAC

AF:

0.441

AC:

1699

ESP6500AA

AF:

0.545

AC:

2215

ESP6500EA

AF:

0.427

AC:

3559

ExAC

AF:

0.423

AC:

51126

Asia WGS

AF:

0.343

AC:

1198

AN:

3478

EpiCase

AF:

0.432

EpiControl

AF:

0.427

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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: 42% of total chromosomes in ExAC -

Jan 11, 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. -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

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 66% of patients studied by a panel of primary immunodeficiencies. Number of patients: 63. Only high quality variants are reported. -

not provided

Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Van Maldergem syndrome 2

Benign:1

Aug 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hennekam lymphangiectasia-lymphedema syndrome 2

Benign:1

Aug 10, 2021

Genome-Nilou Lab

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

0.081

BayesDel_addAF

Benign

-0.72

BayesDel_noAF

Benign

-0.67

CADD

Benign

9.6

(source)

DANN

Benign

0.82

DEOGEN2

Benign

0.046

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.27

LIST_S2

Benign

0.67

MetaRNN

Benign

0.000024

MetaSVM

Benign

-0.93

MutationAssessor

Benign

0.28

PhyloP100

0.15

PrimateAI

Benign

0.36

PROVEAN

Benign

-0.31

REVEL

Benign

0.018

Sift

Benign

0.33

Sift4G

Benign

0.22

Polyphen

0.0020

Vest4

0.081

MPC

0.15

ClinPred

0.0027

GERP RS

-2.6

Varity_R

0.092

gMVP

0.28

Mutation Taster

=87/13

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over