4-186588460-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_005245.4(FAT1):c.*132C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0382 in 1,086,018 control chromosomes in the GnomAD database, including 1,483 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.037 (228 hom., cov: 32)
  • Exomes 𝑓: 0.038 (1255 hom.)
• Consequence: FAT1 NM_005245.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.90

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 4-186588460-G-A is Benign according to our data. Variant chr4-186588460-G-A is described in ClinVar as [Benign]. Clinvar id is 1257852.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.165 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FAT1	NM_005245.4	c.*132C>T		3_prime_UTR_variant	27/27	ENST00000441802.7
FAT1	XM_005262834.4	c.*132C>T		3_prime_UTR_variant	28/28
FAT1	XM_005262835.3	c.*132C>T		3_prime_UTR_variant	28/28
FAT1	XM_006714139.4	c.*132C>T		3_prime_UTR_variant	27/27

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FAT1	ENST00000441802.7	c.*132C>T		3_prime_UTR_variant	27/27	5	NM_005245.4	P1
FAT1	ENST00000512772.5	c.*132C>T		3_prime_UTR_variant	4/4	2
FAT1	ENST00000500085.2	n.1591C>T		non_coding_transcript_exon_variant	3/3	2

Frequencies

GnomAD3 genomes AF: 0.0367 AC: 5589 AN: 152124 Hom.: 223 Cov.: 32

Gnomad AFR AF: 0.00862

Gnomad AMI AF: 0.0461

Gnomad AMR AF: 0.0836

Gnomad ASJ AF: 0.00518

Gnomad EAS AF: 0.174

Gnomad SAS AF: 0.0132

Gnomad FIN AF: 0.0798

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0298

Gnomad OTH AF: 0.0273

GnomAD4 exome AF: 0.0385 AC: 35927 AN: 933774 Hom.: 1255 Cov.: 12 AF XY: 0.0373 AC XY: 17327 AN XY: 463926

Gnomad4 AFR exome AF: 0.00505

Gnomad4 AMR exome AF: 0.120

Gnomad4 ASJ exome AF: 0.00618

Gnomad4 EAS exome AF: 0.183

Gnomad4 SAS exome AF: 0.0121

Gnomad4 FIN exome AF: 0.0687

Gnomad4 NFE exome AF: 0.0321

Gnomad4 OTH exome AF: 0.0379

GnomAD4 genome AF: 0.0368 AC: 5600 AN: 152244 Hom.: 228 Cov.: 32 AF XY: 0.0399 AC XY: 2972 AN XY: 74448

Gnomad4 AFR AF: 0.00859

Gnomad4 AMR AF: 0.0845

Gnomad4 ASJ AF: 0.00518

Gnomad4 EAS AF: 0.175

Gnomad4 SAS AF: 0.0132

Gnomad4 FIN AF: 0.0798

Gnomad4 NFE AF: 0.0298

Gnomad4 OTH AF: 0.0256

Alfa AF: 0.0329 Hom.: 13

Bravo AF: 0.0407

Asia WGS AF: 0.0950 AC: 330 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 12, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
Cadd	Benign	6.5
Dann	Benign	0.76
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs75546828; hg19: chr4-187509614; COSMIC: COSV71676719; COSMIC: COSV71676719;