rs12508222

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

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

The NM_001291303.3(FAT4):c.8482G>A(p.Asp2828Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0141 in 1,613,770 control chromosomes in the GnomAD database, including 1,577 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.028 ( 232 hom., cov: 32)

Exomes 𝑓: 0.013 ( 1345 hom. )

Consequence

FAT4
NM_001291303.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 9.71

Publications

22 publications found

Variant links:

Genes affected

FAT4 (HGNC:23109): (FAT atypical cadherin 4) The protein encoded by this gene is a member of the protocadherin family. This gene may play a role in regulating planar cell polarity (PCP). Studies in mice suggest that loss of PCP signaling may cause cystic kidney disease, and mutations in this gene have been associated with Van Maldergem Syndrome 2. Alternatively spliced transcript variants have been noted for this gene. [provided by RefSeq, Mar 2014]

FAT4 Gene-Disease associations (from GenCC):

FAT4-related neurodevelopmental disorder
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
Hennekam lymphangiectasia-lymphedema syndrome 2
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
van Maldergem syndrome 2
Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
multiple congenital anomalies/dysmorphic syndrome-intellectual disability
Inheritance: AR Classification: STRONG Submitted by: Ambry Genetics
Hennekam syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
van Maldergem syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

FAT4 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=0.003456831).

BP6

Variant 4-125449492-G-A is Benign according to our data. Variant chr4-125449492-G-A is described in ClinVar as Benign. ClinVar VariationId is 380933.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.134 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001291303.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FAT4	NM_001291303.3	MANE Select	c.8482G>A	p.Asp2828Asn	missense	Exon 10 of 18	NP_001278232.1	A0A6Q8JR05
FAT4	NM_001438396.1		c.8482G>A	p.Asp2828Asn	missense	Exon 9 of 17	NP_001425325.1
FAT4	NM_001291285.3		c.8482G>A	p.Asp2828Asn	missense	Exon 10 of 18	NP_001278214.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FAT4	ENST00000394329.9	TSL:5 MANE Select	c.8482G>A	p.Asp2828Asn	missense	Exon 10 of 18	ENSP00000377862.4	A0A6Q8JR05
FAT4	ENST00000335110.5	TSL:1	c.3370G>A	p.Asp1124Asn	missense	Exon 9 of 15	ENSP00000335169.5	Q6V0I7-2
FAT4	ENST00000674496.2		c.3253G>A	p.Asp1085Asn	missense	Exon 9 of 17	ENSP00000501473.2	A0A7P0T1I0

Frequencies

GnomAD3 genomes

AF:

0.0280

AC:

4257

AN:

152008

Hom.:

233

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0322

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.128

Gnomad ASJ

AF:

0.000289

Gnomad EAS

AF:

0.143

Gnomad SAS

AF:

0.0315

Gnomad FIN

AF:

0.000189

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.000471

Gnomad OTH

AF:

0.0258

GnomAD2 exomes

AF:

0.0428

AC:

10698

AN:

249844

AF XY:

0.0357

show subpopulations

Gnomad AFR exome

AF:

0.0339

Gnomad AMR exome

AF:

0.184

Gnomad ASJ exome

AF:

0.000498

Gnomad EAS exome

AF:

0.150

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.000389

Gnomad OTH exome

AF:

0.0284

GnomAD4 exome

AF:

0.0126

AC:

18437

AN:

1461644

Hom.:

1345

Cov.:

AF XY:

0.0121

AC XY:

8801

AN XY:

727112

show subpopulations

African (AFR)

AF:

0.0307

AC:

1028

AN:

33476

American (AMR)

AF:

0.176

AC:

7856

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.000421

AC:

AN:

26126

East Asian (EAS)

AF:

0.146

AC:

5809

AN:

39674

South Asian (SAS)

AF:

0.0250

AC:

2155

AN:

86244

European-Finnish (FIN)

AF:

0.000150

AC:

AN:

53396

Middle Eastern (MID)

AF:

0.00399

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000297

AC:

330

AN:

1111870

Other (OTH)

AF:

0.0202

AC:

1217

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

1007

2014

3020

4027

5034

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

272

544

816

1088

1360

<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:

0.0280

AC:

4260

AN:

152126

Hom.:

232

Cov.:

AF XY:

0.0305

AC XY:

2270

AN XY:

74366

show subpopulations

African (AFR)

AF:

0.0322

AC:

1335

AN:

41510

American (AMR)

AF:

0.128

AC:

1947

AN:

15252

Ashkenazi Jewish (ASJ)

AF:

0.000289

AC:

AN:

3466

East Asian (EAS)

AF:

0.142

AC:

734

AN:

5160

South Asian (SAS)

AF:

0.0311

AC:

150

AN:

4818

European-Finnish (FIN)

AF:

0.000189

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000471

AC:

AN:

67996

Other (OTH)

AF:

0.0270

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

198

396

593

791

989

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

132

176

220

<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:

0.0126

Hom.:

219

Bravo

AF:

0.0383

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.0302

AC:

133

ESP6500EA

AF:

0.00140

AC:

ExAC

AF:

0.0360

AC:

4364

EpiCase

AF:

0.000600

EpiControl

AF:

0.000237

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (4)

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.68

BayesDel_noAF

Benign

-0.61

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.028

Eigen

Uncertain

0.59

Eigen_PC

Pathogenic

0.67

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.94

MetaRNN

Benign

0.0035

MetaSVM

Benign

-0.36

MutationAssessor

Benign

-0.23

PhyloP100

9.7

PrimateAI

Uncertain

0.58

PROVEAN

Benign

1.5

REVEL

Benign

0.22

Sift

Benign

1.0

Sift4G

Uncertain

0.0070

Polyphen

0.99

Vest4

0.49

MPC

0.30

ClinPred

0.045

GERP RS

5.6

Varity_R

0.080

gMVP

0.45

Mutation Taster

=87/13

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