4-186588765-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005245.4(FAT1):c.13594G>A(p.Val4532Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,613,902 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: FAT1 NM_005245.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.05

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.087048024).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FAT1	NM_005245.4	c.13594G>A	p.Val4532Ile	missense_variant	27/27	ENST00000441802.7
FAT1	XM_005262834.4	c.13630G>A	p.Val4544Ile	missense_variant	28/28
FAT1	XM_005262835.3	c.13630G>A	p.Val4544Ile	missense_variant	28/28
FAT1	XM_006714139.4	c.13594G>A	p.Val4532Ile	missense_variant	27/27

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FAT1	ENST00000441802.7	c.13594G>A	p.Val4532Ile	missense_variant	27/27	5	NM_005245.4	P1
FAT1	ENST00000512772.5	c.934G>A	p.Val312Ile	missense_variant	4/4	2
FAT1	ENST00000500085.2	n.1286G>A		non_coding_transcript_exon_variant	3/3	2
FAT1	ENST00000507105.1			downstream_gene_variant		3

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152192 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461710 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727136

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152192 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74342

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

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

Dec 07, 2021

The c.13594G>A (p.V4532I) alteration is located in exon 27 (coding exon 26) of the FAT1 gene. This alteration results from a G to A substitution at nucleotide position 13594, causing the valine (V) at amino acid position 4532 to be replaced by an isoleucine (I). 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	0.076
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
Cadd	Benign	8.3
Dann	Benign	0.65
DEOGEN2	Benign	0.083	T;T
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.47
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.74	T;T
M_CAP	Benign	0.0071	T
MetaRNN	Benign	0.087	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L;.
MutationTaster	Benign	0.76	N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.16	N;.
REVEL	Benign	0.063
Sift	Benign	0.27	T;.
Sift4G	Benign	0.15	T;T
Polyphen		0.0020	B;.
Vest4		0.071
MutPred		0.11		Loss of catalytic residue at V4532 (P = 0.0799);.;
MVP		0.21
MPC		0.078
ClinPred		0.32	T
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.015
gMVP		0.036

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

LitVar

Other links and lift over

dbSNP: rs1394546790; hg19: chr4-187509919;