4-186588700-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_005245.4(FAT1):​c.13659C>G​(p.Cys4553Trp) 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 pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Consequence

FAT1
NM_005245.4 missense

Scores

3
12
4

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.389
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 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.772

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
FAT1NM_005245.4 linkc.13659C>G p.Cys4553Trp missense_variant Exon 27 of 27 ENST00000441802.7 NP_005236.2 Q14517
FAT1XM_005262834.4 linkc.13695C>G p.Cys4565Trp missense_variant Exon 28 of 28 XP_005262891.1
FAT1XM_005262835.3 linkc.13695C>G p.Cys4565Trp missense_variant Exon 28 of 28 XP_005262892.1
FAT1XM_006714139.4 linkc.13659C>G p.Cys4553Trp 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.13659C>G p.Cys4553Trp missense_variant Exon 27 of 27 5 NM_005245.4 ENSP00000406229.2 Q14517
FAT1ENST00000512772.5 linkc.996C>G p.Cys332Trp missense_variant Exon 4 of 4 2 ENSP00000424157.1 H0Y9H4
FAT1ENST00000500085.2 linkn.1351C>G non_coding_transcript_exon_variant Exon 3 of 3 2

Frequencies

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

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.69
BayesDel_addAF
Pathogenic
0.17
D
BayesDel_noAF
Uncertain
0.010
CADD
Benign
15
DANN
Uncertain
0.98
DEOGEN2
Uncertain
0.50
T;T
Eigen
Benign
-0.58
Eigen_PC
Benign
-0.72
FATHMM_MKL
Benign
0.75
D
LIST_S2
Uncertain
0.87
D;D
M_CAP
Uncertain
0.15
D
MetaRNN
Pathogenic
0.77
D;D
MetaSVM
Uncertain
-0.18
T
MutationAssessor
Uncertain
2.4
M;.
PrimateAI
Uncertain
0.75
T
PROVEAN
Uncertain
-3.4
D;.
REVEL
Uncertain
0.44
Sift
Uncertain
0.0020
D;.
Sift4G
Uncertain
0.0030
D;D
Polyphen
1.0
D;.
Vest4
0.83
MutPred
0.45
Gain of catalytic residue at C4553 (P = 0.0135);.;
MVP
0.14
MPC
0.57
ClinPred
0.98
D
GERP RS
-8.4
Varity_R
0.67
gMVP
0.66

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: chr4-187509854; API