dbSNP rs1039808: FAT4:p.Ala807Glu (chr4-125318831-C-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001291303.3(FAT4):c.2420C>A(p.Ala807Glu) variant causes a missense change. The variant allele was found at a frequency of 0.0000103 in 1,461,866 control chromosomes in the GnomAD database, with no homozygous occurrence. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A807V) has been classified as Benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000010 ( 0 hom. )

Consequence

FAT4
NM_001291303.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.68

Publications

0 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: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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.2420C>A	p.Ala807Glu	missense	Exon 2 of 18	NP_001278232.1
FAT4	NM_001438396.1		c.2420C>A	p.Ala807Glu	missense	Exon 1 of 17	NP_001425325.1
FAT4	NM_001291285.3		c.2420C>A	p.Ala807Glu	missense	Exon 2 of 18	NP_001278214.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
FAT4	ENST00000394329.9	TSL:5 MANE Select	c.2420C>A	p.Ala807Glu	missense	Exon 2 of 18	ENSP00000377862.4
FAT4	ENST00000678072.1		n.26C>A		non_coding_transcript_exon	Exon 1 of 2
FAT4	ENST00000674496.2		c.-55+2854C>A		intron	N/A	ENSP00000501473.2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.0000103

AC:

AN:

1461866

Hom.:

Cov.:

AF XY:

0.0000124

AC XY:

AN XY:

727238

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53400

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000117

AC:

AN:

1112010

Other (OTH)

AF:

0.0000166

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.452

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.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.29

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.53

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.059

Eigen

Uncertain

0.34

Eigen_PC

Uncertain

0.37

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.96

M_CAP

Benign

0.012

MetaRNN

Uncertain

0.69

MetaSVM

Benign

-0.75

MutationAssessor

Benign

0.33

PhyloP100

3.7

PrimateAI

Uncertain

0.71

PROVEAN

Benign

-0.52

REVEL

Benign

0.13

Sift

Benign

0.48

Sift4G

Uncertain

0.0090

Polyphen

0.94

Vest4

0.42

MutPred

0.52

Loss of catalytic residue at V806 (P = 0.3119)

MVP

0.13

MPC

0.30

ClinPred

0.62

GERP RS

5.1

Varity_R

0.27

gMVP

0.38

Mutation Taster

=77/23

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over