Genetic Variant FAT4:p.Asp2674Val (chr4-125449031-A-T) – ACMG Classification: Benign (-11 pts)

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_ModerateBP6BS1BS2

The NM_001291303.3(FAT4):c.8021A>T(p.Asp2674Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00281 in 1,613,802 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D2674A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0019 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0029 ( 6 hom. )

Consequence

FAT4
NM_001291303.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:3

Conservation

PhyloP100: 9.14

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):

FAT4-related neurodevelopmental disorder
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
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

new If you want to explore the variant's impact on the transcript NM_001291303.3, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -11 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.08642647).

BP6

Variant 4-125449031-A-T is Benign according to our data. Variant chr4-125449031-A-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 420323.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00187 (284/152214) while in subpopulation NFE AF = 0.00347 (236/68012). AF 95% confidence interval is 0.00311. There are 0 homozygotes in GnomAd4. There are 113 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 6 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	UniProt
FAT4	NM_001291303.3	MANE Select	c.8021A>T	p.Asp2674Val	missense	Exon 10 of 18	NP_001278232.1	A0A6Q8JR05
FAT4	NM_001438396.1		c.8021A>T	p.Asp2674Val	missense	Exon 9 of 17	NP_001425325.1
FAT4	NM_001291285.3		c.8021A>T	p.Asp2674Val	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.8021A>T	p.Asp2674Val	missense	Exon 10 of 18	ENSP00000377862.4	A0A6Q8JR05
FAT4	ENST00000335110.5	TSL:1	c.2909A>T	p.Asp970Val	missense	Exon 9 of 15	ENSP00000335169.5	Q6V0I7-2
FAT4	ENST00000674496.2		c.2792A>T	p.Asp931Val	missense	Exon 9 of 17	ENSP00000501473.2	A0A7P0T1I0

Frequencies

GnomAD3 genomes

AF:

0.00187

AC:

284

AN:

152096

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000525

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00347

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.00138

AC:

345

AN:

249764

AF XY:

0.00131

show subpopulations

Gnomad AFR exome

AF:

0.000705

Gnomad AMR exome

AF:

0.000463

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000926

Gnomad NFE exome

AF:

0.00259

Gnomad OTH exome

AF:

0.00132

GnomAD4 exome

AF:

0.00291

AC:

4255

AN:

1461588

Hom.:

Cov.:

AF XY:

0.00288

AC XY:

2092

AN XY:

727092

show subpopulations

African (AFR)

AF:

0.000478

AC:

AN:

33460

American (AMR)

AF:

0.000514

AC:

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26110

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39690

South Asian (SAS)

AF:

0.000615

AC:

AN:

86246

European-Finnish (FIN)

AF:

0.0000562

AC:

AN:

53394

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00363

AC:

4034

AN:

1111824

Other (OTH)

AF:

0.00202

AC:

122

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

226

453

679

906

1132

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

156

312

468

624

780

<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:

0.00187

AC:

284

AN:

152214

Hom.:

Cov.:

AF XY:

0.00152

AC XY:

113

AN XY:

74458

show subpopulations

African (AFR)

AF:

0.000722

AC:

AN:

41538

American (AMR)

AF:

0.000524

AC:

AN:

15260

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00104

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00347

AC:

236

AN:

68012

Other (OTH)

AF:

0.00237

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.00169

Hom.:

Bravo

AF:

0.00190

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00322

EpiControl

AF:

0.00225

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (5)

FAT4-related disorder (2)

Van Maldergem syndrome 2 (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Uncertain

0.070

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.13

Eigen

Pathogenic

0.69

Eigen_PC

Pathogenic

0.73

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.90

M_CAP

Benign

0.041

MetaRNN

Benign

0.086

MetaSVM

Benign

-0.81

MutationAssessor

Benign

1.9

PhyloP100

9.1

PrimateAI

Benign

0.43

PROVEAN

Benign

-2.0

REVEL

Uncertain

0.40

Sift

Benign

0.47

Sift4G

Pathogenic

0.0

Varity_R

0.17

gMVP

0.72

Mutation Taster

=46/54

disease causing

(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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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