rs3733414

Variant names:

• chr4-186708616-A-C
• rs3733414
• NM_005245.4:c.1212T>G

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Benign. The variant received -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. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S404G) has been classified as Uncertain significance.

• 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
• Publications: 38 publications found

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

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005245.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FAT1	NM_005245.4	MANE Select	c.1212T>G	p.Ser404Arg	missense	Exon 2 of 27	NP_005236.2
	FAT1	NM_001440456.1		c.1212T>G	p.Ser404Arg	missense	Exon 2 of 28	NP_001427385.1
	FAT1	NM_001440457.1		c.1212T>G	p.Ser404Arg	missense	Exon 2 of 28	NP_001427386.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FAT1	ENST00000441802.7	TSL:5 MANE Select	c.1212T>G	p.Ser404Arg	missense	Exon 2 of 27	ENSP00000406229.2
	FAT1	ENST00000509647.1	TSL:1	c.1212T>G	p.Ser404Arg	missense	Exon 2 of 2	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

GnomAD2 exomes AF: 0.559 AC: 139284 AN: 249180 AF XY: 0.566

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 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

African (AFR) AF: 0.267 AC: 8926 AN: 33478

American (AMR) AF: 0.541 AC: 24187 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.625 AC: 16328 AN: 26136

East Asian (EAS) AF: 0.221 AC: 8757 AN: 39700

South Asian (SAS) AF: 0.508 AC: 43849 AN: 86248

European-Finnish (FIN) AF: 0.637 AC: 33985 AN: 53382

Middle Eastern (MID) AF: 0.550 AC: 3172 AN: 5768

European-Non Finnish (NFE) AF: 0.648 AC: 720084 AN: 1111826

Other (OTH) AF: 0.577 AC: 34806 AN: 60366

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

African (AFR) AF: 0.282 AC: 11680 AN: 41470

American (AMR) AF: 0.555 AC: 8492 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.637 AC: 2205 AN: 3464

East Asian (EAS) AF: 0.241 AC: 1245 AN: 5164

South Asian (SAS) AF: 0.479 AC: 2303 AN: 4808

European-Finnish (FIN) AF: 0.622 AC: 6555 AN: 10538

Middle Eastern (MID) AF: 0.582 AC: 171 AN: 294

European-Non Finnish (NFE) AF: 0.651 AC: 44271 AN: 67968

Other (OTH) AF: 0.534 AC: 1127 AN: 2110

Alfa AF: 0.602 Hom.: 133306

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

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Nov 11, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 29748316)

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.43
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Uncertain	0.86	D
MetaRNN	Benign	0.0000063	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	1.3	L
PhyloP100		0.45
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.64	N
REVEL	Benign	0.14
Sift	Benign	0.53	T
Sift4G	Benign	0.35	T
Polyphen		0.13	B
Vest4		0.29
MutPred		0.40		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
Mutation Taster		=91/9	polymorphism (auto)

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

Other links and lift over

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