4-186621773-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_005245.4(FAT1):c.4813A>G(p.Asn1605Asp) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00264 in 1,550,142 control chromosomes in the GnomAD database, including 89 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.013 ( 50 hom., cov: 33)

Exomes 𝑓: 0.0015 ( 39 hom. )

Consequence

FAT1
NM_005245.4 missense, splice_region

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 8.02

Publications

6 publications found

Variant links:

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]

FAT1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.006181717).

BP6

Variant 4-186621773-T-C is Benign according to our data. Variant chr4-186621773-T-C is described in ClinVar as Benign. ClinVar VariationId is 778168.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0133 (2032/152266) while in subpopulation AFR AF = 0.0469 (1946/41520). AF 95% confidence interval is 0.0451. There are 50 homozygotes in GnomAd4. There are 942 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 50 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAT1	NM_005245.4 link	c.4813A>G	p.Asn1605Asp	missense_variant, splice_region_variant	Exon 10 of 27	ENST00000441802.7	NP_005236.2	Q14517
FAT1	NM_001440456.1 link	c.4813A>G	p.Asn1605Asp	missense_variant, splice_region_variant	Exon 10 of 28		NP_001427385.1
FAT1	NM_001440457.1 link	c.4813A>G	p.Asn1605Asp	missense_variant, splice_region_variant	Exon 10 of 28		NP_001427386.1
FAT1	NM_001440455.1 link	c.4813A>G	p.Asn1605Asp	missense_variant, splice_region_variant	Exon 10 of 27		NP_001427384.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FAT1	ENST00000441802.7 link	c.4813A>G	p.Asn1605Asp	missense_variant, splice_region_variant	Exon 10 of 27	5	NM_005245.4	ENSP00000406229.2		Q14517

Frequencies

GnomAD3 genomes

AF:

0.0133

AC:

2017

AN:

152148

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0466

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00334

Gnomad ASJ

AF:

0.000865

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000147

Gnomad OTH

AF:

0.00813

GnomAD2 exomes

AF:

0.00379

AC:

678

AN:

178806

AF XY:

0.00286

show subpopulations

Gnomad AFR exome

AF:

0.0497

Gnomad AMR exome

AF:

0.00187

Gnomad ASJ exome

AF:

0.000726

Gnomad EAS exome

AF:

0.0000683

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000273

Gnomad OTH exome

AF:

0.00178

GnomAD4 exome

AF:

0.00148

AC:

2067

AN:

1397876

Hom.:

Cov.:

AF XY:

0.00127

AC XY:

875

AN XY:

689924

show subpopulations

African (AFR)

AF:

0.0513

AC:

1612

AN:

31432

American (AMR)

AF:

0.00220

AC:

AN:

33604

Ashkenazi Jewish (ASJ)

AF:

0.000760

AC:

AN:

23678

East Asian (EAS)

AF:

0.00

AC:

AN:

38950

South Asian (SAS)

AF:

0.0000517

AC:

AN:

77404

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48026

Middle Eastern (MID)

AF:

0.00670

AC:

AN:

5522

European-Non Finnish (NFE)

AF:

0.000144

AC:

156

AN:

1081476

Other (OTH)

AF:

0.00287

AC:

166

AN:

57784

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

100

200

300

400

500

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

128

192

256

320

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0133

AC:

2032

AN:

152266

Hom.:

Cov.:

AF XY:

0.0127

AC XY:

942

AN XY:

74464

show subpopulations

African (AFR)

AF:

0.0469

AC:

1946

AN:

41520

American (AMR)

AF:

0.00334

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.000865

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.000414

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.000188

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000147

AC:

AN:

68028

Other (OTH)

AF:

0.00804

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

178

268

357

446

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00443

Hom.:

Bravo

AF:

0.0148

ESP6500AA

AF:

0.0368

AC:

131

ESP6500EA

AF:

0.000253

AC:

ExAC

AF:

0.00367

AC:

439

Asia WGS

AF:

0.00346

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Mar 31, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 21, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.34

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.52

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.40

T;T

Eigen

Uncertain

0.56

Eigen_PC

Uncertain

0.56

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.95

D;T

MetaRNN

Benign

0.0062

T;T

MetaSVM

Benign

-0.73

MutationAssessor

Benign

1.3

L;.

PhyloP100

8.0

PrimateAI

Uncertain

0.69

PROVEAN

Pathogenic

-4.7

D;.

REVEL

Uncertain

0.35

Sift

Uncertain

0.0070

D;.

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;.

Vest4

0.83

MVP

0.44

MPC

0.53

ClinPred

0.024

GERP RS

5.1

Varity_R

0.69

gMVP

0.41

Mutation Taster

=80/20

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over