chr4-125316816-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001291303.3(FAT4):c.405C>T(p.Phe135Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.209 in 1,613,560 control chromosomes in the GnomAD database, including 36,566 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.17 ( 2631 hom., cov: 32)

Exomes 𝑓: 0.21 ( 33935 hom. )

Consequence

FAT4
NM_001291303.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 2.37

Publications

12 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.48).

BP6

Variant 4-125316816-C-T is Benign according to our data. Variant chr4-125316816-C-T is described in ClinVar as [Benign]. Clinvar id is 380815.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=2.37 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.223 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAT4	NM_001291303.3 link	c.405C>T	p.Phe135Phe	synonymous_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.405C>T	p.Phe135Phe	synonymous_variant	Exon 2 of 18	5	NM_001291303.3	ENSP00000377862.4		A0A6Q8JR05
FAT4	ENST00000674496.2 link	c.-55+839C>T		intron_variant	Intron 1 of 16			ENSP00000501473.2		A0A7P0T1I0

Frequencies

GnomAD3 genomes

AF:

0.174

AC:

26505

AN:

152028

Hom.:

2630

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0876

Gnomad AMI

AF:

0.264

Gnomad AMR

AF:

0.150

Gnomad ASJ

AF:

0.203

Gnomad EAS

AF:

0.112

Gnomad SAS

AF:

0.161

Gnomad FIN

AF:

0.238

Gnomad MID

AF:

0.142

Gnomad NFE

AF:

0.226

Gnomad OTH

AF:

0.179

GnomAD2 exomes

AF:

0.185

AC:

46000

AN:

248304

AF XY:

0.189

show subpopulations

Gnomad AFR exome

AF:

0.0852

Gnomad AMR exome

AF:

0.124

Gnomad ASJ exome

AF:

0.210

Gnomad EAS exome

AF:

0.116

Gnomad FIN exome

AF:

0.226

Gnomad NFE exome

AF:

0.223

Gnomad OTH exome

AF:

0.201

GnomAD4 exome

AF:

0.212

AC:

310007

AN:

1461414

Hom.:

33935

Cov.:

AF XY:

0.211

AC XY:

153756

AN XY:

726984

show subpopulations

African (AFR)

AF:

0.0806

AC:

2698

AN:

33476

American (AMR)

AF:

0.126

AC:

5632

AN:

44678

Ashkenazi Jewish (ASJ)

AF:

0.213

AC:

5555

AN:

26134

East Asian (EAS)

AF:

0.107

AC:

4246

AN:

39682

South Asian (SAS)

AF:

0.169

AC:

14553

AN:

86238

European-Finnish (FIN)

AF:

0.225

AC:

12000

AN:

53300

Middle Eastern (MID)

AF:

0.151

AC:

870

AN:

5768

European-Non Finnish (NFE)

AF:

0.227

AC:

252689

AN:

1111770

Other (OTH)

AF:

0.195

AC:

11764

AN:

60368

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

17570

35139

52709

70278

87848

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

8542

17084

25626

34168

42710

<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:

0.174

AC:

26508

AN:

152146

Hom.:

2631

Cov.:

AF XY:

0.174

AC XY:

12907

AN XY:

74364

show subpopulations

African (AFR)

AF:

0.0876

AC:

3639

AN:

41532

American (AMR)

AF:

0.150

AC:

2298

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.203

AC:

706

AN:

3472

East Asian (EAS)

AF:

0.112

AC:

579

AN:

5166

South Asian (SAS)

AF:

0.161

AC:

775

AN:

4822

European-Finnish (FIN)

AF:

0.238

AC:

2521

AN:

10574

Middle Eastern (MID)

AF:

0.146

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.226

AC:

15336

AN:

67972

Other (OTH)

AF:

0.176

AC:

371

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1126

2252

3378

4504

5630

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

292

584

876

1168

1460

<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:

0.203

Hom.:

6365

Bravo

AF:

0.162

Asia WGS

AF:

0.140

AC:

489

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

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 34% of patients studied by a panel of primary immunodeficiencies. Number of patients: 32. Only high quality variants are reported. -

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: 19% of total chromosomes in ExAC -

Jan 14, 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 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

- -

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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.48

CADD

Benign

(source)

DANN

Benign

0.91

PhyloP100

2.4

Mutation Taster

=99/1

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