4-186588822-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_005245.4(FAT1):c.13537A>G(p.Arg4513Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: FAT1 NM_005245.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.45

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

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FAT1	NM_005245.4	c.13537A>G	p.Arg4513Gly	missense_variant	27/27	ENST00000441802.7
FAT1	XM_005262834.4	c.13573A>G	p.Arg4525Gly	missense_variant	28/28
FAT1	XM_005262835.3	c.13573A>G	p.Arg4525Gly	missense_variant	28/28
FAT1	XM_006714139.4	c.13537A>G	p.Arg4513Gly	missense_variant	27/27

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FAT1	ENST00000441802.7	c.13537A>G	p.Arg4513Gly	missense_variant	27/27	5	NM_005245.4	P1
FAT1	ENST00000512772.5	c.877A>G	p.Arg293Gly	missense_variant	4/4	2
FAT1	ENST00000507105.1	c.841A>G	p.Arg281Gly	missense_variant	5/5	3
FAT1	ENST00000500085.2	n.1229A>G		non_coding_transcript_exon_variant	3/3	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 16, 2022

The c.13537A>G (p.R4513G) alteration is located in exon 27 (coding exon 26) of the FAT1 gene. This alteration results from a A to G substitution at nucleotide position 13537, causing the arginine (R) at amino acid position 4513 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.099	T
BayesDel_noAF	Benign	-0.38
Cadd	Benign	16
Dann	Uncertain	0.98
DEOGEN2	Benign	0.10	T;T
Eigen	Benign	-0.0027
Eigen_PC	Benign	0.015
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.87	D;D
M_CAP	Benign	0.026	D
MetaRNN	Uncertain	0.53	D;D
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	1.6	L;.
MutationTaster	Benign	0.98	D
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.66	N;.
REVEL	Benign	0.20
Sift	Benign	0.18	T;.
Sift4G	Benign	0.58	T;T
Polyphen		0.0030	B;.
Vest4		0.86
MutPred		0.13		Loss of glycosylation at P4518 (P = 0.0306);.;
MVP		0.30
MPC		0.13
ClinPred		0.31	T
GERP RS		2.7
Varity_R		0.17
gMVP		0.33

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-187509976;