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GeneBe

4-125316448-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001291303.3(FAT4):c.37T>C(p.Trp13Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 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)

Consequence

FAT4
NM_001291303.3 missense

Scores

1
1
17

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.719
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.096790075).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
FAT4NM_001291303.3 linkuse as main transcriptc.37T>C p.Trp13Arg missense_variant 2/18 ENST00000394329.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
FAT4ENST00000394329.9 linkuse as main transcriptc.37T>C p.Trp13Arg missense_variant 2/185 NM_001291303.3 P1
FAT4ENST00000674496.2 linkuse as main transcriptc.-55+471T>C intron_variant

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingInvitaeAug 09, 2021In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt FAT4 protein function. This variant has not been reported in the literature in individuals affected with FAT4-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces tryptophan with arginine at codon 13 of the FAT4 protein (p.Trp13Arg). The tryptophan residue is weakly conserved and there is a moderate physicochemical difference between tryptophan and arginine. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.12
BayesDel_addAF
Benign
-0.15
T
BayesDel_noAF
Benign
-0.46
Cadd
Benign
18
Dann
Benign
0.56
DEOGEN2
Benign
0.054
T
Eigen
Benign
-1.0
Eigen_PC
Benign
-0.93
FATHMM_MKL
Benign
0.58
D
LIST_S2
Benign
0.45
T
M_CAP
Benign
0.031
D
MetaRNN
Benign
0.097
T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
-0.34
N
MutationTaster
Benign
1.0
N
PrimateAI
Uncertain
0.50
T
PROVEAN
Benign
-0.69
N
REVEL
Benign
0.087
Sift
Benign
0.96
T
Sift4G
Pathogenic
0.0
D
Polyphen
0.0
B
Vest4
0.21
MutPred
0.47
Gain of disorder (P = 0.0013);
MVP
0.17
MPC
0.27
ClinPred
0.071
T
GERP RS
-0.74
Varity_R
0.055
gMVP
0.62

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-126237603; API