4-186588654-C-A

Variant names:

• chr4-186588654-C-A
• rs771965001
• NM_005245.4:c.13705G>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_005245.4(FAT1):​c.13705G>T​(p.Asp4569Tyr) variant causes a missense change. 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. D4569H) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FAT1 NM_005245.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.79
• Publications: 0 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: 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FAT1	NM_005245.4	MANE Select	c.13705G>T	p.Asp4569Tyr	missense	Exon 27 of 27	NP_005236.2	Q14517
	FAT1	NM_001440456.1		c.13741G>T	p.Asp4581Tyr	missense	Exon 28 of 28	NP_001427385.1
	FAT1	NM_001440457.1		c.13741G>T	p.Asp4581Tyr	missense	Exon 28 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.13705G>T	p.Asp4569Tyr	missense	Exon 27 of 27	ENSP00000406229.2	Q14517
	FAT1	ENST00000917425.1		c.13705G>T	p.Asp4569Tyr	missense	Exon 27 of 27	ENSP00000587484.1
	FAT1	ENST00000917424.1		c.13699G>T	p.Asp4567Tyr	missense	Exon 27 of 27	ENSP00000587483.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Uncertain	0.046	T
BayesDel_noAF	Benign	-0.17
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.14	T
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.098	D
MetaRNN	Uncertain	0.71	D
MetaSVM	Benign	-0.53	T
MutationAssessor	Benign	1.5	L
PhyloP100		5.8
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.97	N
REVEL	Uncertain	0.32
Sift	Uncertain	0.0060	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.65
MutPred		0.34		Gain of glycosylation at Y4564 (P = 7e-04)
MVP		0.66
MPC		0.52
ClinPred		0.82	D
GERP RS		5.3
Varity_R		0.35
gMVP		0.37
Mutation Taster		=58/42	polymorphism

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

Other links and lift over

dbSNP: rs771965001; hg19: chr4-187509808;