4-186588632-G-C

Variant summary

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

The NM_005245.4(FAT1):ā€‹c.13727C>Gā€‹(p.Thr4576Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,204 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 6.8e-7 ( 0 hom. )

Consequence

FAT1
NM_005245.4 missense

Scores

2
17

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.20
Variant links:
Genes affected
FAT1 (HGNC:3595): (FAT atypical cadherin 1) This gene is an ortholog of the Drosophila fat gene, which encodes a tumor suppressor essential for controlling cell proliferation during Drosophila development. The gene product is a member of the cadherin superfamily, a group of integral membrane proteins characterized by the presence of cadherin-type repeats. In addition to containing 34 tandem cadherin-type repeats, the gene product has five epidermal growth factor (EGF)-like repeats and one laminin A-G domain. This gene is expressed at high levels in a number of fetal epithelia. Its product probably functions as an adhesion molecule and/or signaling receptor, and is likely to be important in developmental processes and cell communication. Transcript variants derived from alternative splicing and/or alternative promoter usage exist, but they have not been fully described. [provided by RefSeq, Jul 2008]

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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=0.19415715).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
FAT1NM_005245.4 linkc.13727C>G p.Thr4576Arg missense_variant Exon 27 of 27 ENST00000441802.7 NP_005236.2 Q14517
FAT1XM_005262834.4 linkc.13763C>G p.Thr4588Arg missense_variant Exon 28 of 28 XP_005262891.1
FAT1XM_005262835.3 linkc.13763C>G p.Thr4588Arg missense_variant Exon 28 of 28 XP_005262892.1
FAT1XM_006714139.4 linkc.13727C>G p.Thr4576Arg missense_variant Exon 27 of 27 XP_006714202.1 Q14517

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
FAT1ENST00000441802.7 linkc.13727C>G p.Thr4576Arg missense_variant Exon 27 of 27 5 NM_005245.4 ENSP00000406229.2 Q14517
FAT1ENST00000512772.5 linkc.1064C>G p.Thr355Arg missense_variant Exon 4 of 4 2 ENSP00000424157.1 H0Y9H4
FAT1ENST00000500085.2 linkn.1419C>G non_coding_transcript_exon_variant Exon 3 of 3 2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461204
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
726824
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
9.00e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.080
BayesDel_addAF
Benign
-0.060
T
BayesDel_noAF
Benign
-0.32
CADD
Benign
19
DANN
Benign
0.70
DEOGEN2
Benign
0.12
T;T
Eigen
Benign
-0.12
Eigen_PC
Benign
0.000063
FATHMM_MKL
Uncertain
0.83
D
LIST_S2
Uncertain
0.91
D;D
M_CAP
Benign
0.030
D
MetaRNN
Benign
0.19
T;T
MetaSVM
Benign
-0.93
T
MutationAssessor
Benign
1.1
L;.
PrimateAI
Benign
0.35
T
PROVEAN
Benign
-0.93
N;.
REVEL
Benign
0.11
Sift
Benign
0.14
T;.
Sift4G
Benign
0.12
T;T
Polyphen
0.47
P;.
Vest4
0.26
MutPred
0.16
Loss of glycosylation at T4576 (P = 0.0214);.;
MVP
0.62
MPC
0.21
ClinPred
0.32
T
GERP RS
5.3
Varity_R
0.054
gMVP
0.34

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.070
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: chr4-187509786; API