Genetic Variant FAT1:p.Gly4570Val (chr4-186588650-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_005245.4(FAT1):c.13709G>T(p.Gly4570Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 16/22 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. G4570D) 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: 2.52

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.13709G>T	p.Gly4570Val	missense	Exon 27 of 27	NP_005236.2	Q14517
FAT1	NM_001440456.1		c.13745G>T	p.Gly4582Val	missense	Exon 28 of 28	NP_001427385.1
FAT1	NM_001440457.1		c.13745G>T	p.Gly4582Val	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.13709G>T	p.Gly4570Val	missense	Exon 27 of 27	ENSP00000406229.2	Q14517
FAT1	ENST00000917425.1		c.13709G>T	p.Gly4570Val	missense	Exon 27 of 27	ENSP00000587484.1
FAT1	ENST00000917424.1		c.13703G>T	p.Gly4568Val	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

Benign

0.10

BayesDel_addAF

Benign

-0.034

BayesDel_noAF

Benign

-0.29

CADD

Benign

(source)

DANN

Benign

0.91

DEOGEN2

Benign

0.10

Eigen

Benign

0.13

Eigen_PC

Benign

0.13

FATHMM_MKL

Uncertain

0.86

LIST_S2

Uncertain

0.94

M_CAP

Benign

0.058

MetaRNN

Uncertain

0.43

MetaSVM

Benign

-0.67

MutationAssessor

Benign

1.6

PhyloP100

2.5

PrimateAI

Benign

0.41

PROVEAN

Benign

-0.41

REVEL

Benign

0.12

Sift

Benign

0.16

Sift4G

Benign

0.23

Polyphen

0.92

Vest4

0.55

MutPred

0.14

Gain of glycosylation at S4566 (P = 0.0856)

MVP

0.58

MPC

0.25

ClinPred

0.53

GERP RS

4.2

Varity_R

0.12

gMVP

0.27

Mutation Taster

=66/34

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