rs1554000415

Variant names:

• chr4-186706731-CGGGT-C
• rs1554000415
• NM_005245.4:c.3093_3096delACCC

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_005245.4(FAT1):​c.3093_3096delACCC​(p.Pro1032CysfsTer11) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FAT1 NM_005245.4 frameshift
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 10.0
• Publications: 3 publications found

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

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FAT1	NM_005245.4	MANE Select	c.3093_3096delACCC	p.Pro1032CysfsTer11	frameshift	Exon 2 of 27	NP_005236.2	Q14517
	FAT1	NM_001440456.1		c.3093_3096delACCC	p.Pro1032CysfsTer11	frameshift	Exon 2 of 28	NP_001427385.1
	FAT1	NM_001440457.1		c.3093_3096delACCC	p.Pro1032CysfsTer11	frameshift	Exon 2 of 28	NP_001427386.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FAT1	ENST00000441802.7	TSL:5 MANE Select	c.3093_3096delACCC	p.Pro1032CysfsTer11	frameshift	Exon 2 of 27	ENSP00000406229.2	Q14517
	FAT1	ENST00000917425.1		c.3093_3096delACCC	p.Pro1032CysfsTer11	frameshift	Exon 2 of 27	ENSP00000587484.1
	FAT1	ENST00000917424.1		c.3093_3096delACCC	p.Pro1032CysfsTer11	frameshift	Exon 2 of 27	ENSP00000587483.1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		10
Mutation Taster		=0/200	disease causing (fs/PTC)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1554000415; hg19: chr4-187627885;