NM_001291303.3:c.8021A>T

Variant names:

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBS1_SupportingBS2

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).

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

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

BP4

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

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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAdExome4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAT4	NM_001291303.3 link	c.8021A>T	p.Asp2674Val	missense_variant	Exon 10 of 18	ENST00000394329.9	NP_001278232.1	Q6V0I7A0A6Q8JR05X2G5I7B3KU84

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
FAT4	ENST00000394329.9 link	c.8021A>T	p.Asp2674Val	missense_variant	Exon 10 of 18	5	NM_001291303.3	ENSP00000377862.4	A0A6Q8JR05
FAT4	ENST00000335110.5 link	c.2909A>T	p.Asp970Val	missense_variant	Exon 9 of 15	1		ENSP00000335169.5	Q6V0I7-2
FAT4	ENST00000674496.2 link	c.2792A>T	p.Asp931Val	missense_variant	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

GnomAD3 exomes

AF:

0.00138

AC:

345

AN:

249764

Hom.:

AF XY:

0.00131

AC XY:

178

AN XY:

135400

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 SAS exome

AF:

0.000523

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

Gnomad4 AFR exome

AF:

0.000478

Gnomad4 AMR exome

AF:

0.000514

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000615

Gnomad4 FIN exome

AF:

0.0000562

Gnomad4 NFE exome

AF:

0.00363

Gnomad4 OTH exome

AF:

0.00202

GnomAD4 genome

AF:

0.00187

AC:

284

AN:

152214

Hom.:

Cov.:

AF XY:

0.00152

AC XY:

113

AN XY:

74458

show subpopulations

Gnomad4 AFR

AF:

0.000722

Gnomad4 AMR

AF:

0.000524

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00104

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00347

Gnomad4 OTH

AF:

0.00237

Alfa

AF:

0.00169

Hom.:

Bravo

AF:

0.00190

TwinsUK

AF:

0.00297

AC:

ALSPAC

AF:

0.00493

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00221

AC:

ExAC

AF:

0.00122

AC:

148

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00322

EpiControl

AF:

0.00225

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3Benign:2

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

FAT4: BP4 -

May 14, 2018

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The D2672V variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The D2672V variant is observed in 315/126102 (0.25%) alleles from individuals of European background in large population cohorts (Lek et al., 2016). The D2672V variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. GeneDx interprets D2672V as a variant of uncertain significance. -

Oct 26, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The FAT4 c.8015A>T; p.Asp2672Val variant (rs138655269), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 420323). This variant is found in the non-Finnish European population with an overall allele frequency of 0.25% (324/128362 alleles) in the Genome Aggregation Database. The aspartate at codon 2672 is highly conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.396). Due to limited information, the clinical significance of the p.Asp2672Val variant is uncertain at this time. -

Nov 03, 2021

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Van Maldergem syndrome 2

Uncertain:2

Nov 16, 2016

Undiagnosed Diseases Network, NIH

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 01, 2021

UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

The FAT4 c.8015A>T (p.Asp2672Val) missense variant is located in exon 10, and results in a single amino acid substitution from an aspartic acid to a valine. This variant was detected in the compound heterozygous state in an individual with Van Maldergem syndrome 2; this individual was also reported to have diploid/triploid mosaicism (ClinVar entry from Undiagnosed Diseases Network). The variant was also described in the homozygous state in a 3 year-old male with suspected Van Maldergem syndrome; he also had compound heterozygous variants in CYP21A2 and was diagnosed with congenital adrenal hyperplasia (PMID: 31384091). FAT4 c.8015A>T (p.Asp2672Val) is present in human population databases (allele frequency 383 alleles/281150 total alleles: 0.001). Due to the limited information regarding this variant, it is classified as a VUS. -

FAT4-related disorder

Uncertain:1Benign:1

Jan 01, 2024

Daryl Scott Lab, Baylor College of Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM3, PP3 -

Sep 02, 2022

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Uncertain

0.070

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.13

T;.

Eigen

Pathogenic

0.69

Eigen_PC

Pathogenic

0.73

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.90

D;D

M_CAP

Benign

0.041

MetaRNN

Benign

0.086

T;T

MetaSVM

Benign

-0.81

MutationAssessor

Benign

1.9

L;.

PrimateAI

Benign

0.43

PROVEAN

Benign

-2.0

N;N

REVEL

Uncertain

0.40

Sift

Benign

0.47

T;T

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;D

Vest4

0.77

MVP

0.63

MPC

0.77

ClinPred

0.046

GERP RS

5.9

Varity_R

0.17

gMVP

0.72

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over