chr4-186603866-A-G

Variant names:

• chr4-186603866-A-G
• rs2637777
• NM_005245.4:c.10660T>C

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.10660T>C​(p.Ser3554Pro) 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. 14/22 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. S3554A) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FAT1 NM_005245.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.198
• 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]

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=0.07876921).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAT1	NM_005245.4	c.10660T>C	p.Ser3554Pro	missense_variant	Exon 19 of 27	ENST00000441802.7	NP_005236.2
FAT1	NM_001440456.1	c.10660T>C	p.Ser3554Pro	missense_variant	Exon 19 of 28		NP_001427385.1
FAT1	NM_001440457.1	c.10660T>C	p.Ser3554Pro	missense_variant	Exon 19 of 28		NP_001427386.1
FAT1	NM_001440455.1	c.10660T>C	p.Ser3554Pro	missense_variant	Exon 19 of 27		NP_001427384.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FAT1	ENST00000441802.7	c.10660T>C	p.Ser3554Pro	missense_variant	Exon 19 of 27	5	NM_005245.4	ENSP00000406229.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 37

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	10
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.42	T;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.82	T;T
M_CAP	Benign	0.0058	T
MetaRNN	Benign	0.079	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	L;.
PhyloP100		0.20
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-2.2	N;.
REVEL	Benign	0.044
Sift	Uncertain	0.020	D;.
Sift4G	Uncertain	0.016	D;D
Polyphen		0.0030	B;.
Vest4		0.14
MutPred		0.32		Loss of glycosylation at T3553 (P = 0.0494);.;
MVP		0.12
MPC		0.12
ClinPred		0.18	T
GERP RS		2.2
Varity_R		0.36
gMVP		0.43
Mutation Taster		=82/18	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: rs2637777; hg19: chr4-187525020;