Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001291303.3(FAT4):c.7358G>T(p.Ser2453Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00129 in 1,613,542 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0032 ( 4 hom., cov: 32)

Exomes 𝑓: 0.0011 ( 7 hom. )

Consequence

FAT4
NM_001291303.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 2.75

Publications

6 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=0.011135817).

BP6

Variant 4-125446451-G-T is Benign according to our data. Variant chr4-125446451-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 435176.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00319 (485/152190) while in subpopulation AMR AF = 0.00852 (130/15266). AF 95% confidence interval is 0.00733. There are 4 homozygotes in GnomAd4. There are 246 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 4 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001291303.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
FAT4	NM_001291303.3	MANE Select	c.7358G>T	p.Ser2453Ile	missense	Exon 9 of 18	NP_001278232.1
FAT4	NM_001438396.1		c.7358G>T	p.Ser2453Ile	missense	Exon 8 of 17	NP_001425325.1
FAT4	NM_001291285.3		c.7358G>T	p.Ser2453Ile	missense	Exon 9 of 18	NP_001278214.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
FAT4	ENST00000394329.9	TSL:5 MANE Select	c.7358G>T	p.Ser2453Ile	missense	Exon 9 of 18	ENSP00000377862.4
FAT4	ENST00000335110.5	TSL:1	c.2246G>T	p.Ser749Ile	missense	Exon 8 of 15	ENSP00000335169.5
FAT4	ENST00000674496.2		c.2129G>T	p.Ser710Ile	missense	Exon 8 of 17	ENSP00000501473.2

Frequencies

GnomAD3 genomes

AF:

0.00319

AC:

485

AN:

152072

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00616

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00853

Gnomad ASJ

AF:

0.000866

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00118

Gnomad OTH

AF:

0.00671

GnomAD2 exomes

AF:

0.00167

AC:

419

AN:

250898

AF XY:

0.00141

show subpopulations

Gnomad AFR exome

AF:

0.00653

Gnomad AMR exome

AF:

0.00391

Gnomad ASJ exome

AF:

0.00209

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00117

Gnomad OTH exome

AF:

0.00360

GnomAD4 exome

AF:

0.00109

AC:

1592

AN:

1461352

Hom.:

Cov.:

AF XY:

0.00105

AC XY:

760

AN XY:

726990

show subpopulations

African (AFR)

AF:

0.00652

AC:

218

AN:

33450

American (AMR)

AF:

0.00396

AC:

177

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.00146

AC:

AN:

26102

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39694

South Asian (SAS)

AF:

0.0000928

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53406

Middle Eastern (MID)

AF:

0.00537

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000874

AC:

971

AN:

1111604

Other (OTH)

AF:

0.00244

AC:

147

AN:

60368

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

164

247

329

411

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

108

144

180

<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:

0.00319

AC:

485

AN:

152190

Hom.:

Cov.:

AF XY:

0.00331

AC XY:

246

AN XY:

74416

show subpopulations

African (AFR)

AF:

0.00614

AC:

255

AN:

41538

American (AMR)

AF:

0.00852

AC:

130

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.000866

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5162

South Asian (SAS)

AF:

0.000207

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00118

AC:

AN:

67998

Other (OTH)

AF:

0.00664

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

112

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.00150

Hom.:

Bravo

AF:

0.00388

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.00658

AC:

ESP6500EA

AF:

0.000930

AC:

ExAC

AF:

0.00147

AC:

178

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00164

EpiControl

AF:

0.00166

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

FAT4-related disorder (1)

Inborn genetic diseases (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.40

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.33

Eigen

Benign

-0.11

Eigen_PC

Benign

-0.047

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.85

M_CAP

Benign

0.032

MetaRNN

Benign

0.011

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.68

PhyloP100

2.7

PrimateAI

Uncertain

0.49

PROVEAN

Uncertain

-4.0

REVEL

Benign

0.091

Sift

Uncertain

0.0050

Sift4G

Uncertain

0.0030

Polyphen

0.97

Vest4

0.64

MVP

0.19

MPC

0.60

ClinPred

0.037

GERP RS

3.6

Varity_R

0.18

gMVP

0.57

Mutation Taster

=66/34

polymorphism

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over