rs1298865

chr4-186595726-A-Gchr4-186595726-A-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_005245.4(FAT1):c.13101T>C(p.Ser4367=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.386 in 1,613,448 control chromosomes in the GnomAD database, including 128,044 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.47 (18538 hom., cov: 32)
  • Exomes 𝑓: 0.38 (109506 hom.)
• Consequence: FAT1 NM_005245.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.424

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP6: Variant 4-186595726-A-G is Benign according to our data. Variant chr4-186595726-A-G is described in ClinVar as [Benign]. Clinvar id is 1273862.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.424 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.661 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FAT1	NM_005245.4	c.13101T>C	p.Ser4367=	synonymous_variant	26/27	ENST00000441802.7
FAT1	XM_005262834.4	c.13101T>C	p.Ser4367=	synonymous_variant	26/28
FAT1	XM_005262835.3	c.13101T>C	p.Ser4367=	synonymous_variant	26/28
FAT1	XM_006714139.4	c.13101T>C	p.Ser4367=	synonymous_variant	26/27

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FAT1	ENST00000441802.7	c.13101T>C	p.Ser4367=	synonymous_variant	26/27	5	NM_005245.4	P1

Frequencies

GnomAD3 genomes AF: 0.473 AC: 71923 AN: 151918 Hom.: 18513 Cov.: 32

Gnomad AFR AF: 0.668

Gnomad AMI AF: 0.308

Gnomad AMR AF: 0.525

Gnomad ASJ AF: 0.457

Gnomad EAS AF: 0.609

Gnomad SAS AF: 0.262

Gnomad FIN AF: 0.392

Gnomad MID AF: 0.459

Gnomad NFE AF: 0.365

Gnomad OTH AF: 0.453

GnomAD3 exomes AF: 0.426 AC: 106179 AN: 249204 Hom.: 24855 AF XY: 0.408 AC XY: 55114 AN XY: 135192

Gnomad AFR exome AF: 0.675

Gnomad AMR exome AF: 0.589

Gnomad ASJ exome AF: 0.458

Gnomad EAS exome AF: 0.621

Gnomad SAS exome AF: 0.257

Gnomad FIN exome AF: 0.388

Gnomad NFE exome AF: 0.362

Gnomad OTH exome AF: 0.406

GnomAD4 exome AF: 0.377 AC: 551315 AN: 1461412 Hom.: 109506 Cov.: 39 AF XY: 0.372 AC XY: 270371 AN XY: 727004

Gnomad4 AFR exome AF: 0.676

Gnomad4 AMR exome AF: 0.578

Gnomad4 ASJ exome AF: 0.459

Gnomad4 EAS exome AF: 0.646

Gnomad4 SAS exome AF: 0.259

Gnomad4 FIN exome AF: 0.384

Gnomad4 NFE exome AF: 0.356

Gnomad4 OTH exome AF: 0.396

GnomAD4 genome AF: 0.474 AC: 71998 AN: 152036 Hom.: 18538 Cov.: 32 AF XY: 0.475 AC XY: 35258 AN XY: 74296

Gnomad4 AFR AF: 0.667

Gnomad4 AMR AF: 0.526

Gnomad4 ASJ AF: 0.457

Gnomad4 EAS AF: 0.610

Gnomad4 SAS AF: 0.261

Gnomad4 FIN AF: 0.392

Gnomad4 NFE AF: 0.365

Gnomad4 OTH AF: 0.450

Alfa AF: 0.403 Hom.: 16883

Bravo AF: 0.500

Asia WGS AF: 0.445 AC: 1548 AN: 3478

EpiCase AF: 0.362

EpiControl AF: 0.362

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 11, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
Cadd	Benign	3.3
Dann	Benign	0.61

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: rs1298865; hg19: chr4-187516880; COSMIC: COSV71672634; COSMIC: COSV71672634;