4-125408758-A-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001291303.3(FAT4):c.5884A>T(p.Thr1962Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000139 in 1,440,914 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

FAT4
NM_001291303.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.96

Publications

1 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: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.05340779).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAT4	NM_001291303.3 link	c.5884A>T	p.Thr1962Ser	missense_variant	Exon 5 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.5884A>T	p.Thr1962Ser	missense_variant	Exon 5 of 18	5	NM_001291303.3	ENSP00000377862.4	A0A6Q8JR05
FAT4	ENST00000335110.5 link	c.778A>T	p.Thr260Ser	missense_variant	Exon 4 of 15	1		ENSP00000335169.5	Q6V0I7-2
FAT4	ENST00000674496.2 link	c.655A>T	p.Thr219Ser	missense_variant	Exon 4 of 17			ENSP00000501473.2	A0A7P0T1I0

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000854

AC:

AN:

234104

AF XY:

0.00000789

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000627

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000139

AC:

AN:

1440914

Hom.:

Cov.:

AF XY:

0.00000140

AC XY:

AN XY:

716392

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32766

American (AMR)

AF:

0.0000474

AC:

AN:

42200

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25096

East Asian (EAS)

AF:

0.00

AC:

AN:

39354

South Asian (SAS)

AF:

0.00

AC:

AN:

82662

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52570

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5636

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1101174

Other (OTH)

AF:

0.00

AC:

AN:

59456

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.650

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Mar 23, 2016

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.71

CADD

Benign

(source)

DANN

Benign

0.83

DEOGEN2

Benign

0.039

T;.

Eigen

Benign

-0.54

Eigen_PC

Benign

-0.32

FATHMM_MKL

Benign

0.73

LIST_S2

Benign

0.50

T;T

M_CAP

Benign

0.0059

MetaRNN

Benign

0.053

T;T

MetaSVM

Benign

-0.91

MutationAssessor

Benign

-0.34

N;.

PhyloP100

2.0

PrimateAI

Benign

0.36

PROVEAN

Benign

0.36

N;N

REVEL

Benign

0.043

Sift

Benign

0.72

T;T

Sift4G

Benign

1.0

T;T

Polyphen

0.019

B;B

Vest4

0.13

MutPred

0.43

Gain of disorder (P = 0.0782);.;

MVP

0.093

MPC

0.14

ClinPred

0.042

GERP RS

4.0

Varity_R

0.054

gMVP

0.15

Mutation Taster

=76/24

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over