rs3733414

Positions:

• chr4-186708616-A-C
• chr4-186708616-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005245.4(FAT1):​c.1212T>G​(p.Ser404Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.603 in 1,613,644 control chromosomes in the GnomAD database, including 303,297 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.52 (22599 hom., cov: 32)
  • Exomes 𝑓: 0.61 (280698 hom.)
• Consequence: FAT1 NM_005245.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.450

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=6.3383923E-6).
• BP6: Variant 4-186708616-A-C is Benign according to our data. Variant chr4-186708616-A-C is described in ClinVar as [Benign]. Clinvar id is 1288791.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.646 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FAT1	NM_005245.4	c.1212T>G	p.Ser404Arg	missense_variant	2/27	ENST00000441802.7	NP_005236.2
FAT1	XM_005262834.4	c.1212T>G	p.Ser404Arg	missense_variant	2/28		XP_005262891.1
FAT1	XM_005262835.3	c.1212T>G	p.Ser404Arg	missense_variant	2/28		XP_005262892.1
FAT1	XM_006714139.4	c.1212T>G	p.Ser404Arg	missense_variant	2/27		XP_006714202.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FAT1	ENST00000441802.7	c.1212T>G	p.Ser404Arg	missense_variant	2/27	5	NM_005245.4	ENSP00000406229.2
FAT1	ENST00000509647.1	c.1212T>G	p.Ser404Arg	missense_variant	2/2	1		ENSP00000423736.1

Frequencies

GnomAD3 genomes AF: 0.518 AC: 78637 AN: 151900 Hom.: 22592 Cov.: 32

Gnomad AFR AF: 0.282

Gnomad AMI AF: 0.684

Gnomad AMR AF: 0.555

Gnomad ASJ AF: 0.637

Gnomad EAS AF: 0.241

Gnomad SAS AF: 0.478

Gnomad FIN AF: 0.622

Gnomad MID AF: 0.585

Gnomad NFE AF: 0.651

Gnomad OTH AF: 0.534

GnomAD3 exomes AF: 0.559 AC: 139284 AN: 249180 Hom.: 41387 AF XY: 0.566 AC XY: 76475 AN XY: 135176

Gnomad AFR exome AF: 0.273

Gnomad AMR exome AF: 0.537

Gnomad ASJ exome AF: 0.627

Gnomad EAS exome AF: 0.228

Gnomad SAS exome AF: 0.506

Gnomad FIN exome AF: 0.627

Gnomad NFE exome AF: 0.652

Gnomad OTH exome AF: 0.579

GnomAD4 exome AF: 0.612 AC: 894094 AN: 1461626 Hom.: 280698 Cov.: 67 AF XY: 0.610 AC XY: 443625 AN XY: 727094

Gnomad4 AFR exome AF: 0.267

Gnomad4 AMR exome AF: 0.541

Gnomad4 ASJ exome AF: 0.625

Gnomad4 EAS exome AF: 0.221

Gnomad4 SAS exome AF: 0.508

Gnomad4 FIN exome AF: 0.637

Gnomad4 NFE exome AF: 0.648

Gnomad4 OTH exome AF: 0.577

GnomAD4 genome AF: 0.518 AC: 78673 AN: 152018 Hom.: 22599 Cov.: 32 AF XY: 0.515 AC XY: 38242 AN XY: 74298

Gnomad4 AFR AF: 0.282

Gnomad4 AMR AF: 0.555

Gnomad4 ASJ AF: 0.637

Gnomad4 EAS AF: 0.241

Gnomad4 SAS AF: 0.479

Gnomad4 FIN AF: 0.622

Gnomad4 NFE AF: 0.651

Gnomad4 OTH AF: 0.534

Alfa AF: 0.616 Hom.: 71451

Bravo AF: 0.499

TwinsUK AF: 0.649 AC: 2406

ALSPAC AF: 0.645 AC: 2484

ESP6500AA AF: 0.302 AC: 1123

ESP6500EA AF: 0.653 AC: 5346

ExAC AF: 0.557 AC: 67337

Asia WGS AF: 0.361 AC: 1258 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 11, 2018	This variant is associated with the following publications: (PMID: 29748316) -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	14
DANN	Benign	0.95
DEOGEN2	Benign	0.12	T;T;T
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.43
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Uncertain	0.86	D;D;D
MetaRNN	Benign	0.0000063	T;T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	1.3	L;.;.
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.64	N;.;N
REVEL	Benign	0.14
Sift	Benign	0.53	T;.;T
Sift4G	Benign	0.35	T;T;.
Polyphen		0.13	B;.;.
Vest4		0.29
MutPred		0.40		Gain of MoRF binding (P = 0.0196);Gain of MoRF binding (P = 0.0196);Gain of MoRF binding (P = 0.0196);
MPC		0.13
ClinPred		0.0036	T
GERP RS		1.4
Varity_R		0.059
gMVP		0.39

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: rs3733414; hg19: chr4-187629770; COSMIC: COSV71672025;