Genetic Variant NM_001367949.2:c.1235C>T (chr11-92353347-C-T) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BA1

The NM_001367949.2(FAT3):c.1235C>T(p.Ser412Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.058 in 1,613,420 control chromosomes in the GnomAD database, including 3,418 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 (no stars).

Frequency

Genomes: 𝑓 0.078 ( 655 hom., cov: 32)

Exomes 𝑓: 0.056 ( 2763 hom. )

Consequence

FAT3
NM_001367949.2 missense

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: 1.16

Publications

8 publications found

Variant links:

Genes affected

FAT3 (HGNC:23112): (FAT atypical cadherin 3) Predicted to enable calcium ion binding activity. Predicted to be involved in cell-cell adhesion. Predicted to act upstream of or within several processes, including negative regulation of dendrite development; neuron migration; and retina layer formation. Predicted to be located in dendrite and plasma membrane. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

FAT3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0023308992).

BP6

Variant 11-92353347-C-T is Benign according to our data. Variant chr11-92353347-C-T is described in ClinVar as Benign. ClinVar VariationId is 3055330.Status of the report is no_assertion_criteria_provided, 0 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.148 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001367949.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FAT3	NM_001367949.2	MANE Select	c.1235C>T	p.Ser412Phe	missense	Exon 2 of 28	NP_001354878.1	Q8TDW7-1
FAT3	NM_001008781.3		c.1235C>T	p.Ser412Phe	missense	Exon 2 of 26	NP_001008781.2	Q8TDW7-3
FAT3	NM_001378141.1		c.1235C>T	p.Ser412Phe	missense	Exon 2 of 4	NP_001365070.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FAT3	ENST00000525166.6	TSL:5 MANE Select	c.1235C>T	p.Ser412Phe	missense	Exon 2 of 28	ENSP00000432586.2	Q8TDW7-1
	FAT3	ENST00000409404.6	TSL:5	c.1235C>T	p.Ser412Phe	missense	Exon 1 of 25	ENSP00000387040.2	Q8TDW7-3

Frequencies

GnomAD3 genomes

AF:

0.0777

AC:

11823

AN:

152132

Hom.:

652

Cov.:

show subpopulations

Gnomad AFR

AF:

0.151

Gnomad AMI

AF:

0.0230

Gnomad AMR

AF:

0.0531

Gnomad ASJ

AF:

0.0894

Gnomad EAS

AF:

0.000386

Gnomad SAS

AF:

0.00663

Gnomad FIN

AF:

0.0268

Gnomad MID

AF:

0.0605

Gnomad NFE

AF:

0.0580

Gnomad OTH

AF:

0.0674

GnomAD2 exomes

AF:

0.0462

AC:

11416

AN:

247230

AF XY:

0.0436

show subpopulations

Gnomad AFR exome

AF:

0.153

Gnomad AMR exome

AF:

0.0305

Gnomad ASJ exome

AF:

0.0859

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0270

Gnomad NFE exome

AF:

0.0540

Gnomad OTH exome

AF:

0.0490

GnomAD4 exome

AF:

0.0560

AC:

81782

AN:

1461170

Hom.:

2763

Cov.:

AF XY:

0.0540

AC XY:

39229

AN XY:

726826

show subpopulations

African (AFR)

AF:

0.158

AC:

5302

AN:

33470

American (AMR)

AF:

0.0323

AC:

1438

AN:

44584

Ashkenazi Jewish (ASJ)

AF:

0.0895

AC:

2337

AN:

26118

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39688

South Asian (SAS)

AF:

0.00936

AC:

807

AN:

86204

European-Finnish (FIN)

AF:

0.0274

AC:

1460

AN:

53298

Middle Eastern (MID)

AF:

0.0671

AC:

387

AN:

5766

European-Non Finnish (NFE)

AF:

0.0600

AC:

66664

AN:

1111682

Other (OTH)

AF:

0.0561

AC:

3385

AN:

60360

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

4773

9546

14320

19093

23866

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2584

5168

7752

10336

12920

<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:

0.0776

AC:

11822

AN:

152250

Hom.:

655

Cov.:

AF XY:

0.0748

AC XY:

5569

AN XY:

74422

show subpopulations

African (AFR)

AF:

0.151

AC:

6260

AN:

41534

American (AMR)

AF:

0.0529

AC:

809

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.0894

AC:

310

AN:

3466

East Asian (EAS)

AF:

0.000386

AC:

AN:

5176

South Asian (SAS)

AF:

0.00663

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.0268

AC:

284

AN:

10610

Middle Eastern (MID)

AF:

0.0616

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0580

AC:

3945

AN:

68028

Other (OTH)

AF:

0.0667

AC:

141

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

552

1104

1657

2209

2761

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

130

260

390

520

650

<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:

0.0634

Hom.:

1706

Bravo

AF:

0.0831

TwinsUK

AF:

0.0591

AC:

219

ALSPAC

AF:

0.0576

AC:

222

ESP6500AA

AF:

0.138

AC:

511

ESP6500EA

AF:

0.0557

AC:

457

ExAC

AF:

0.0461

AC:

5566

Asia WGS

AF:

0.0140

AC:

AN:

3478

EpiCase

AF:

0.0568

EpiControl

AF:

0.0588

ClinVar

ClinVar submissions

Significance:Benign

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

FAT3-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.44

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.13

Eigen

Benign

-0.11

Eigen_PC

Benign

-0.10

FATHMM_MKL

Benign

0.57

MetaRNN

Benign

0.0023

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.8

PhyloP100

1.2

PrimateAI

Benign

0.36

PROVEAN

Benign

-1.8

REVEL

Benign

0.089

Sift

Benign

0.035

Vest4

0.52

ClinPred

0.0051

GERP RS

4.7

Varity_R

0.096

gMVP

0.38

Mutation Taster

=91/9

polymorphism (auto)

(source)

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

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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