FAT1 p.Ser404Arg

Variant names:

• chr4-186708618-T-G
• NM_005245.4:c.1210A>C
• FAT1 p.Ser404Arg

Your query was ambiguous. Multiple possible variants found:

• chr4-186708618-T-G
• chr4-186708616-A-T
• chr4-186708616-A-C
• chr4-186708616-ACT-GCG
• chr4-186708616-ACT-TCG
• chr4-186708616-ACT-CCG

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005245.4(FAT1):​c.1210A>C​(p.Ser404Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S404G) 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: 2.27
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14457583).

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.1210A>C	p.Ser404Arg	missense	Exon 2 of 27	NP_005236.2	Q14517
	FAT1	NM_001440456.1		c.1210A>C	p.Ser404Arg	missense	Exon 2 of 28	NP_001427385.1
	FAT1	NM_001440457.1		c.1210A>C	p.Ser404Arg	missense	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.1210A>C	p.Ser404Arg	missense	Exon 2 of 27	ENSP00000406229.2	Q14517
	FAT1	ENST00000509647.1	TSL:1	c.1210A>C	p.Ser404Arg	missense	Exon 2 of 2	ENSP00000423736.1	D6RCE4
	FAT1	ENST00000917425.1		c.1210A>C	p.Ser404Arg	missense	Exon 2 of 27	ENSP00000587484.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 39

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Uncertain	0.024	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	21
DANN	Benign	0.97
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.0088
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-0.75	T
MutationAssessor	Benign	1.3	L
PhyloP100		2.3
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.64	N
REVEL	Benign	0.17
Sift	Benign	0.53	T
Sift4G	Benign	0.35	T
Varity_R		0.17
gMVP		0.39
Mutation Taster		=79/21	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr4-187629772;