Genetic Variant FAT1:p.Glu4558Gln (chr4-186588687-C-G) – 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_005245.4(FAT1):c.13672G>C(p.Glu4558Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. E4558K) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

FAT1
NM_005245.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.56

Publications

0 publications found

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]

FAT1 Gene-Disease associations (from GenCC):

focal segmental glomerulosclerosis
Inheritance: AR Classification: STRONG Submitted by: ClinGen

FAT1 links:

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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_005245.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FAT1	NM_005245.4	MANE Select	c.13672G>C	p.Glu4558Gln	missense	Exon 27 of 27	NP_005236.2	Q14517
FAT1	NM_001440456.1		c.13708G>C	p.Glu4570Gln	missense	Exon 28 of 28	NP_001427385.1
FAT1	NM_001440457.1		c.13708G>C	p.Glu4570Gln	missense	Exon 28 of 28	NP_001427386.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FAT1	ENST00000441802.7	TSL:5 MANE Select	c.13672G>C	p.Glu4558Gln	missense	Exon 27 of 27	ENSP00000406229.2	Q14517
FAT1	ENST00000917425.1		c.13672G>C	p.Glu4558Gln	missense	Exon 27 of 27	ENSP00000587484.1
FAT1	ENST00000917424.1		c.13666G>C	p.Glu4556Gln	missense	Exon 27 of 27	ENSP00000587483.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.38

BayesDel_addAF

Uncertain

0.077

BayesDel_noAF

Benign

-0.13

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.21

Eigen

Uncertain

0.48

Eigen_PC

Uncertain

0.51

FATHMM_MKL

Uncertain

0.97

LIST_S2

Pathogenic

0.97

M_CAP

Benign

0.084

MetaRNN

Uncertain

0.50

MetaSVM

Uncertain

-0.26

MutationAssessor

Benign

1.5

PhyloP100

7.6

PrimateAI

Uncertain

0.59

PROVEAN

Benign

-0.79

REVEL

Uncertain

0.34

Sift

Uncertain

0.0060

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.59

MutPred

0.32

Gain of glycosylation at S4562 (P = 0.0304)

MVP

0.74

MPC

0.50

ClinPred

0.88

GERP RS

5.5

Varity_R

0.33

gMVP

0.22

Mutation Taster

=64/36

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over