dbSNP rs2306990: FAT1:c.12258-30G>A (chr4-186597822-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_005245.4(FAT1):c.12258-30G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.344 in 1,591,240 control chromosomes in the GnomAD database, including 99,153 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.32 ( 8715 hom., cov: 32)

Exomes 𝑓: 0.35 ( 90438 hom. )

Consequence

FAT1
NM_005245.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.538

Publications

13 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 Gene-Disease associations (from GenCC):

focal segmental glomerulosclerosis
Inheritance: AR Classification: STRONG Submitted by: ClinGen

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 (BayesDel_noAF=-0.83).

BP6

Variant 4-186597822-C-T is Benign according to our data. Variant chr4-186597822-C-T is described in ClinVar as Benign. ClinVar VariationId is 1261827.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.55 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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
FAT1	NM_005245.4	MANE Select	c.12258-30G>A	intron	N/A	NP_005236.2	Q14517
FAT1	NM_001440456.1		c.12258-30G>A	intron	N/A	NP_001427385.1
FAT1	NM_001440457.1		c.12258-30G>A	intron	N/A	NP_001427386.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
FAT1	ENST00000441802.7	TSL:5 MANE Select	c.12258-30G>A	intron	N/A	ENSP00000406229.2	Q14517
FAT1	ENST00000917425.1		c.12258-30G>A	intron	N/A	ENSP00000587484.1
FAT1	ENST00000917424.1		c.12252-30G>A	intron	N/A	ENSP00000587483.1

Frequencies

GnomAD3 genomes

AF:

0.321

AC:

48760

AN:

151824

Hom.:

8707

Cov.:

show subpopulations

Gnomad AFR

AF:

0.183

Gnomad AMI

AF:

0.307

Gnomad AMR

AF:

0.456

Gnomad ASJ

AF:

0.389

Gnomad EAS

AF:

0.567

Gnomad SAS

AF:

0.249

Gnomad FIN

AF:

0.385

Gnomad MID

AF:

0.382

Gnomad NFE

AF:

0.348

Gnomad OTH

AF:

0.341

GnomAD2 exomes

AF:

0.374

AC:

91479

AN:

244414

AF XY:

0.364

show subpopulations

Gnomad AFR exome

AF:

0.176

Gnomad AMR exome

AF:

0.550

Gnomad ASJ exome

AF:

0.389

Gnomad EAS exome

AF:

0.580

Gnomad FIN exome

AF:

0.383

Gnomad NFE exome

AF:

0.347

Gnomad OTH exome

AF:

0.371

GnomAD4 exome

AF:

0.347

AC:

499198

AN:

1439298

Hom.:

90438

Cov.:

AF XY:

0.344

AC XY:

246383

AN XY:

717046

show subpopulations

African (AFR)

AF:

0.170

AC:

5620

AN:

33088

American (AMR)

AF:

0.535

AC:

23675

AN:

44214

Ashkenazi Jewish (ASJ)

AF:

0.387

AC:

10049

AN:

25942

East Asian (EAS)

AF:

0.586

AC:

23177

AN:

39560

South Asian (SAS)

AF:

0.248

AC:

21250

AN:

85520

European-Finnish (FIN)

AF:

0.379

AC:

20172

AN:

53266

Middle Eastern (MID)

AF:

0.351

AC:

2010

AN:

5722

European-Non Finnish (NFE)

AF:

0.341

AC:

372840

AN:

1092406

Other (OTH)

AF:

0.342

AC:

20405

AN:

59580

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

16083

32166

48250

64333

80416

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

11956

23912

35868

47824

59780

<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:

0.321

AC:

48774

AN:

151942

Hom.:

8715

Cov.:

AF XY:

0.326

AC XY:

24192

AN XY:

74210

show subpopulations

African (AFR)

AF:

0.183

AC:

7575

AN:

41492

American (AMR)

AF:

0.457

AC:

6973

AN:

15258

Ashkenazi Jewish (ASJ)

AF:

0.389

AC:

1349

AN:

3466

East Asian (EAS)

AF:

0.567

AC:

2913

AN:

5134

South Asian (SAS)

AF:

0.249

AC:

1197

AN:

4814

European-Finnish (FIN)

AF:

0.385

AC:

4043

AN:

10500

Middle Eastern (MID)

AF:

0.380

AC:

111

AN:

292

European-Non Finnish (NFE)

AF:

0.347

AC:

23618

AN:

67968

Other (OTH)

AF:

0.340

AC:

716

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1596

3191

4787

6382

7978

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

478

956

1434

1912

2390

<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:

0.341

Hom.:

25696

Bravo

AF:

0.327

Asia WGS

AF:

0.388

AC:

1348

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

1.6

(source)

DANN

Benign

0.45

PhyloP100

-0.54

PromoterAI

-0.0078

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.10

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over