4-125318831-C-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.2420C>T(p.Ala807Val) variant causes a missense change. The variant allele was found at a frequency of 0.438 in 1,613,752 control chromosomes in the GnomAD database, including 157,577 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A807A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.46 ( 16453 hom., cov: 32)

Exomes 𝑓: 0.44 ( 141124 hom. )

Consequence

FAT4
NM_001291303.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 3.68

Publications

43 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=2.4184585E-4).

BP6

Variant 4-125318831-C-T is Benign according to our data. Variant chr4-125318831-C-T is described in ClinVar as Benign. ClinVar VariationId is 380329.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.561 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAT4	NM_001291303.3 link	c.2420C>T	p.Ala807Val	missense_variant	Exon 2 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.2420C>T	p.Ala807Val	missense_variant	Exon 2 of 18	5	NM_001291303.3	ENSP00000377862.4	A0A6Q8JR05
FAT4	ENST00000678072.1 link	n.26C>T		non_coding_transcript_exon_variant	Exon 1 of 2
FAT4	ENST00000674496.2 link	c.-55+2854C>T		intron_variant	Intron 1 of 16			ENSP00000501473.2	A0A7P0T1I0

Frequencies

GnomAD3 genomes

AF:

0.459

AC:

69743

AN:

151826

Hom.:

16427

Cov.:

show subpopulations

Gnomad AFR

AF:

0.566

Gnomad AMI

AF:

0.471

Gnomad AMR

AF:

0.403

Gnomad ASJ

AF:

0.352

Gnomad EAS

AF:

0.244

Gnomad SAS

AF:

0.386

Gnomad FIN

AF:

0.393

Gnomad MID

AF:

0.322

Gnomad NFE

AF:

0.445

Gnomad OTH

AF:

0.439

GnomAD2 exomes

AF:

0.413

AC:

103088

AN:

249352

AF XY:

0.412

show subpopulations

Gnomad AFR exome

AF:

0.573

Gnomad AMR exome

AF:

0.377

Gnomad ASJ exome

AF:

0.365

Gnomad EAS exome

AF:

0.230

Gnomad FIN exome

AF:

0.384

Gnomad NFE exome

AF:

0.443

Gnomad OTH exome

AF:

0.411

GnomAD4 exome

AF:

0.436

AC:

636920

AN:

1461808

Hom.:

141124

Cov.:

AF XY:

0.434

AC XY:

315491

AN XY:

727216

show subpopulations

African (AFR)

AF:

0.576

AC:

19291

AN:

33480

American (AMR)

AF:

0.381

AC:

17027

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.364

AC:

9507

AN:

26134

East Asian (EAS)

AF:

0.236

AC:

9379

AN:

39700

South Asian (SAS)

AF:

0.406

AC:

35028

AN:

86254

European-Finnish (FIN)

AF:

0.390

AC:

20842

AN:

53394

Middle Eastern (MID)

AF:

0.354

AC:

2043

AN:

5768

European-Non Finnish (NFE)

AF:

0.448

AC:

498518

AN:

1111968

Other (OTH)

AF:

0.419

AC:

25285

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

23552

47103

70655

94206

117758

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

15012

30024

45036

60048

75060

<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:

69823

AN:

151944

Hom.:

16453

Cov.:

AF XY:

0.454

AC XY:

33725

AN XY:

74268

show subpopulations

African (AFR)

AF:

0.567

AC:

23475

AN:

41412

American (AMR)

AF:

0.403

AC:

6149

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.352

AC:

1223

AN:

3472

East Asian (EAS)

AF:

0.244

AC:

1256

AN:

5152

South Asian (SAS)

AF:

0.387

AC:

1862

AN:

4814

European-Finnish (FIN)

AF:

0.393

AC:

4147

AN:

10558

Middle Eastern (MID)

AF:

0.336

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.445

AC:

30268

AN:

67950

Other (OTH)

AF:

0.434

AC:

918

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1922

3844

5766

7688

9610

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:

0.442

Hom.:

72226

Bravo

AF:

0.463

TwinsUK

AF:

0.463

AC:

1715

ALSPAC

AF:

0.441

AC:

1700

ESP6500AA

AF:

0.542

AC:

2195

ESP6500EA

AF:

0.426

AC:

3568

ExAC

AF:

0.422

AC:

51004

Asia WGS

AF:

0.341

AC:

1189

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

- -

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. -

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 -

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

0.15

BayesDel_addAF

Benign

-0.72

BayesDel_noAF

Benign

-0.66

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.13

Eigen

Benign

0.15

Eigen_PC

Uncertain

0.23

FATHMM_MKL

Uncertain

0.89

LIST_S2

Uncertain

0.93

MetaRNN

Benign

0.00024

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.84

PhyloP100

3.7

PrimateAI

Uncertain

0.66

PROVEAN

Benign

-1.6

REVEL

Benign

0.12

Sift

Benign

0.20

Sift4G

Uncertain

0.016

Polyphen

0.57

Vest4

0.13

MPC

0.50

ClinPred

0.020

GERP RS

5.1

Varity_R

0.26

gMVP

0.26

Mutation Taster

=97/3

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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