Genetic Variant FAT4:p.Ala4888Gly (chr4-125491479-C-G) – ACMG Classification: Benign (-20 pts)

Variant summary

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

The NM_001291303.3(FAT4):c.14663C>G(p.Ala4888Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00146 in 1,614,118 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0052 ( 8 hom., cov: 33)

Exomes 𝑓: 0.0011 ( 9 hom. )

Consequence

FAT4
NM_001291303.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 3.39

Publications

3 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):

Hennekam lymphangiectasia-lymphedema syndrome 2
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
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=0.007138908).

BP6

Variant 4-125491479-C-G is Benign according to our data. Variant chr4-125491479-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 445551.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 = 0.00516 (785/152238) while in subpopulation AFR AF = 0.0157 (651/41530). AF 95% confidence interval is 0.0147. There are 8 homozygotes in GnomAd4. There are 372 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 8 AR gene

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
FAT4	NM_001291303.3	MANE Select	c.14663C>G	p.Ala4888Gly	missense	Exon 18 of 18	NP_001278232.1
FAT4	NM_001438396.1		c.14663C>G	p.Ala4888Gly	missense	Exon 17 of 17	NP_001425325.1
FAT4	NM_001291285.3		c.14660C>G	p.Ala4887Gly	missense	Exon 18 of 18	NP_001278214.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
FAT4	ENST00000394329.9	TSL:5 MANE Select	c.14663C>G	p.Ala4888Gly	missense	Exon 18 of 18	ENSP00000377862.4
FAT4	ENST00000335110.5	TSL:1	c.9380C>G	p.Ala3127Gly	missense	Exon 15 of 15	ENSP00000335169.5
FAT4	ENST00000674496.2		c.9434C>G	p.Ala3145Gly	missense	Exon 17 of 17	ENSP00000501473.2

Frequencies

GnomAD3 genomes

AF:

0.00515

AC:

784

AN:

152120

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0157

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00406

Gnomad ASJ

AF:

0.00634

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000470

Gnomad OTH

AF:

0.00765

GnomAD2 exomes

AF:

0.00203

AC:

511

AN:

251330

AF XY:

0.00179

show subpopulations

Gnomad AFR exome

AF:

0.0158

Gnomad AMR exome

AF:

0.00191

Gnomad ASJ exome

AF:

0.00953

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000634

Gnomad OTH exome

AF:

0.00310

GnomAD4 exome

AF:

0.00107

AC:

1569

AN:

1461880

Hom.:

Cov.:

AF XY:

0.00103

AC XY:

751

AN XY:

727238

show subpopulations

African (AFR)

AF:

0.0159

AC:

531

AN:

33480

American (AMR)

AF:

0.00215

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00792

AC:

207

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000348

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.00347

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000474

AC:

527

AN:

1112004

Other (OTH)

AF:

0.00305

AC:

184

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

101

202

303

404

505

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

102

136

170

<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:

0.00516

AC:

785

AN:

152238

Hom.:

Cov.:

AF XY:

0.00500

AC XY:

372

AN XY:

74442

show subpopulations

African (AFR)

AF:

0.0157

AC:

651

AN:

41530

American (AMR)

AF:

0.00405

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00634

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000470

AC:

AN:

68016

Other (OTH)

AF:

0.00757

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

118

158

197

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.00211

Hom.:

Bravo

AF:

0.00608

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.0152

AC:

ESP6500EA

AF:

0.000930

AC:

ExAC

AF:

0.00232

AC:

282

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.000763

EpiControl

AF:

0.00113

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Feb 06, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

not provided

Benign:3

May 04, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

FAT4-related disorder

Benign:1

Mar 14, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.50

CADD

Benign

(source)

DANN

Benign

0.92

DEOGEN2

Benign

0.039

Eigen

Benign

-0.27

Eigen_PC

Benign

-0.089

FATHMM_MKL

Uncertain

0.84

LIST_S2

Benign

0.83

MetaRNN

Benign

0.0071

MetaSVM

Benign

-0.85

MutationAssessor

Benign

1.1

PhyloP100

3.4

PrimateAI

Uncertain

0.48

PROVEAN

Benign

-0.45

REVEL

Benign

0.18

Sift

Benign

0.21

Sift4G

Benign

0.68

Polyphen

0.0

Vest4

0.067

MVP

0.14

MPC

0.15

ClinPred

0.011

GERP RS

5.2

Varity_R

0.085

gMVP

0.18

Mutation Taster

=80/20

polymorphism

(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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over