4-186588338-C-T

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.*254G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0198 in 460,638 control chromosomes in the GnomAD database, including 323 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.032 (205 hom., cov: 32)
  • Exomes 𝑓: 0.014 (118 hom.)
• Consequence: FAT1 NM_005245.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0600

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=-0.86).
• BP6: Variant 4-186588338-C-T is Benign according to our data. Variant chr4-186588338-C-T is described in ClinVar as [Benign]. Clinvar id is 1274388.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0924 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FAT1	NM_005245.4	c.*254G>A		3_prime_UTR_variant	27/27	ENST00000441802.7
FAT1	XM_005262834.4	c.*254G>A		3_prime_UTR_variant	28/28
FAT1	XM_005262835.3	c.*254G>A		3_prime_UTR_variant	28/28
FAT1	XM_006714139.4	c.*254G>A		3_prime_UTR_variant	27/27

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FAT1	ENST00000441802.7	c.*254G>A		3_prime_UTR_variant	27/27	5	NM_005245.4	P1
FAT1	ENST00000500085.2	n.1713G>A		non_coding_transcript_exon_variant	3/3	2

Frequencies

GnomAD3 genomes AF: 0.0325 AC: 4938 AN: 152020 Hom.: 204 Cov.: 32

Gnomad AFR AF: 0.0949

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0190

Gnomad ASJ AF: 0.0150

Gnomad EAS AF: 0.0428

Gnomad SAS AF: 0.00724

Gnomad FIN AF: 0.00378

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00462

Gnomad OTH AF: 0.0250

GnomAD4 exome AF: 0.0135 AC: 4169 AN: 308498 Hom.: 118 Cov.: 3 AF XY: 0.0125 AC XY: 1962 AN XY: 157244

Gnomad4 AFR exome AF: 0.0954

Gnomad4 AMR exome AF: 0.0140

Gnomad4 ASJ exome AF: 0.0152

Gnomad4 EAS exome AF: 0.0639

Gnomad4 SAS exome AF: 0.00469

Gnomad4 FIN exome AF: 0.00303

Gnomad4 NFE exome AF: 0.00412

Gnomad4 OTH exome AF: 0.0150

GnomAD4 genome AF: 0.0325 AC: 4944 AN: 152140 Hom.: 205 Cov.: 32 AF XY: 0.0315 AC XY: 2343 AN XY: 74402

Gnomad4 AFR AF: 0.0948

Gnomad4 AMR AF: 0.0190

Gnomad4 ASJ AF: 0.0150

Gnomad4 EAS AF: 0.0429

Gnomad4 SAS AF: 0.00704

Gnomad4 FIN AF: 0.00378

Gnomad4 NFE AF: 0.00462

Gnomad4 OTH AF: 0.0247

Alfa AF: 0.0135 Hom.: 66

Bravo AF: 0.0367

Asia WGS AF: 0.0290 AC: 103 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

Apr 03, 2020

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
Cadd	Benign	0.24
Dann	Benign	0.64

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: rs7680937; hg19: chr4-187509492;