rs1567047

Variant names:

Your query was ambiguous. Multiple possible variants found:

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.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 (★★). Synonymous variant affecting the same amino acid position (i.e. G3526G) has been classified as Likely 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

Publications

35 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=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 VariationId is 380813.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 rank	MANE	Protein	UniProt
FAT4	NM_001291303.3 link	c.10577G>A	p.Gly3526Asp	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.10577G>A	p.Gly3526Asp	missense_variant	Exon 10 of 18	5	NM_001291303.3	ENSP00000377862.4	A0A6Q8JR05
FAT4	ENST00000335110.5 link	c.5465G>A	p.Gly1822Asp	missense_variant	Exon 9 of 15	1		ENSP00000335169.5	Q6V0I7-2
FAT4	ENST00000674496.2 link	c.5348G>A	p.Gly1783Asp	missense_variant	Exon 9 of 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

GnomAD2 exomes

AF:

0.272

AC:

68286

AN:

251236

AF XY:

0.277

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 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

African (AFR)

AF:

0.0556

AC:

1860

AN:

33480

American (AMR)

AF:

0.244

AC:

10934

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.273

AC:

7134

AN:

26136

East Asian (EAS)

AF:

0.411

AC:

16330

AN:

39700

South Asian (SAS)

AF:

0.291

AC:

25076

AN:

86258

European-Finnish (FIN)

AF:

0.239

AC:

12778

AN:

53420

Middle Eastern (MID)

AF:

0.220

AC:

1271

AN:

5768

European-Non Finnish (NFE)

AF:

0.292

AC:

324640

AN:

1111972

Other (OTH)

AF:

0.275

AC:

16632

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

20780

41561

62341

83122

103902

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

10718

21436

32154

42872

53590

<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:

0.224

AC:

34099

AN:

152020

Hom.:

4646

Cov.:

AF XY:

0.223

AC XY:

16603

AN XY:

74296

show subpopulations

African (AFR)

AF:

0.0640

AC:

2657

AN:

41522

American (AMR)

AF:

0.247

AC:

3770

AN:

15250

Ashkenazi Jewish (ASJ)

AF:

0.281

AC:

973

AN:

3468

East Asian (EAS)

AF:

0.407

AC:

2092

AN:

5134

South Asian (SAS)

AF:

0.279

AC:

1339

AN:

4800

European-Finnish (FIN)

AF:

0.241

AC:

2543

AN:

10570

Middle Eastern (MID)

AF:

0.177

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.291

AC:

19774

AN:

67960

Other (OTH)

AF:

0.252

AC:

532

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1262

2523

3785

5046

6308

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

362

724

1086

1448

1810

<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:

0.273

Hom.:

27893

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

Jan 27, 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. -

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 46% of patients studied by a panel of primary immunodeficiencies. Number of patients: 44. Only high quality variants are reported. -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

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: 27% of total chromosomes in ExAC -

Van Maldergem syndrome 2

Benign:2

Aug 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 28, 2019

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

- -

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

0.26

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.23

CADD

Pathogenic

(source)

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;.

PhyloP100

9.8

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

Mutation Taster

=28/72

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