Genetic Variant FAT1:p.Asn1605Tyr (chr4-186621773-T-A) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_005245.4(FAT1):c.4813A>T(p.Asn1605Tyr) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. 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. N1605D) has been classified as Benign.

Frequency

Genomes: not found (cov: 33)

Consequence

FAT1
NM_005245.4 missense, splice_region

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 8.02

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 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.876

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.4813A>T	p.Asn1605Tyr	missense splice_region	Exon 10 of 27	NP_005236.2	Q14517
FAT1	NM_001440456.1		c.4813A>T	p.Asn1605Tyr	missense splice_region	Exon 10 of 28	NP_001427385.1
FAT1	NM_001440457.1		c.4813A>T	p.Asn1605Tyr	missense splice_region	Exon 10 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.4813A>T	p.Asn1605Tyr	missense splice_region	Exon 10 of 27	ENSP00000406229.2	Q14517
FAT1	ENST00000917425.1		c.4813A>T	p.Asn1605Tyr	missense splice_region	Exon 10 of 27	ENSP00000587484.1
FAT1	ENST00000917424.1		c.4813A>T	p.Asn1605Tyr	missense splice_region	Exon 10 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

0.52

BayesDel_addAF

Pathogenic

0.23

BayesDel_noAF

Uncertain

0.090

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.53

Eigen

Pathogenic

0.88

Eigen_PC

Pathogenic

0.77

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.95

M_CAP

Benign

0.059

MetaRNN

Pathogenic

0.88

MetaSVM

Benign

-1.1

MutationAssessor

Pathogenic

3.4

PhyloP100

8.0

PrimateAI

Uncertain

0.68

PROVEAN

Pathogenic

-7.6

REVEL

Uncertain

0.55

Sift

Uncertain

0.0010

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.97

MutPred

0.66

Loss of disorder (P = 0.0912)

MVP

0.44

MPC

0.55

ClinPred

1.0

GERP RS

5.1

Varity_R

0.84

gMVP

0.61

Mutation Taster

=36/64

disease causing

(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