4-125318831-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001291303.3(FAT4):c.2420C>T(p.Ala807Val) variant causes a missense change. The variant allele was found at a frequency of 0.438 in 1,613,752 control chromosomes in the GnomAD database, including 157,577 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A807A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.46 ( 16453 hom., cov: 32)

Exomes 𝑓: 0.44 ( 141124 hom. )

Consequence

FAT4
NM_001291303.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 3.68

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=2.4184585E-4).

BP6

Variant 4-125318831-C-T is Benign according to our data. Variant chr4-125318831-C-T is described in ClinVar as [Benign]. Clinvar id is 380329.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-125318831-C-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.561 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAT4	NM_001291303.3 link	c.2420C>T	p.Ala807Val	missense_variant	Exon 2 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.2420C>T	p.Ala807Val	missense_variant	Exon 2 of 18	5	NM_001291303.3	ENSP00000377862.4	A0A6Q8JR05
FAT4	ENST00000674496.2 link	c.-55+2854C>T		intron_variant	Intron 1 of 16			ENSP00000501473.2	A0A7P0T1I0
FAT4	ENST00000678072.1 link	n.26C>T		non_coding_transcript_exon_variant	Exon 1 of 2

Frequencies

GnomAD3 genomes

AF:

0.459

AC:

69743

AN:

151826

Hom.:

16427

Cov.:

show subpopulations

Gnomad AFR

AF:

0.566

Gnomad AMI

AF:

0.471

Gnomad AMR

AF:

0.403

Gnomad ASJ

AF:

0.352

Gnomad EAS

AF:

0.244

Gnomad SAS

AF:

0.386

Gnomad FIN

AF:

0.393

Gnomad MID

AF:

0.322

Gnomad NFE

AF:

0.445

Gnomad OTH

AF:

0.439

GnomAD3 exomes

AF:

0.413

AC:

103088

AN:

249352

Hom.:

22098

AF XY:

0.412

AC XY:

55724

AN XY:

135282

show subpopulations

Gnomad AFR exome

AF:

0.573

Gnomad AMR exome

AF:

0.377

Gnomad ASJ exome

AF:

0.365

Gnomad EAS exome

AF:

0.230

Gnomad SAS exome

AF:

0.407

Gnomad FIN exome

AF:

0.384

Gnomad NFE exome

AF:

0.443

Gnomad OTH exome

AF:

0.411

GnomAD4 exome

AF:

0.436

AC:

636920

AN:

1461808

Hom.:

141124

Cov.:

AF XY:

0.434

AC XY:

315491

AN XY:

727216

show subpopulations

Gnomad4 AFR exome

AF:

0.576

Gnomad4 AMR exome

AF:

0.381

Gnomad4 ASJ exome

AF:

0.364

Gnomad4 EAS exome

AF:

0.236

Gnomad4 SAS exome

AF:

0.406

Gnomad4 FIN exome

AF:

0.390

Gnomad4 NFE exome

AF:

0.448

Gnomad4 OTH exome

AF:

0.419

GnomAD4 genome

AF:

0.460

AC:

69823

AN:

151944

Hom.:

16453

Cov.:

AF XY:

0.454

AC XY:

33725

AN XY:

74268

show subpopulations

Gnomad4 AFR

AF:

0.567

Gnomad4 AMR

AF:

0.403

Gnomad4 ASJ

AF:

0.352

Gnomad4 EAS

AF:

0.244

Gnomad4 SAS

AF:

0.387

Gnomad4 FIN

AF:

0.393

Gnomad4 NFE

AF:

0.445

Gnomad4 OTH

AF:

0.434

Alfa

AF:

0.435

Hom.:

37251

Bravo

AF:

0.463

TwinsUK

AF:

0.463

AC:

1715

ALSPAC

AF:

0.441

AC:

1700

ESP6500AA

AF:

0.542

AC:

2195

ESP6500EA

AF:

0.426

AC:

3568

ExAC

AF:

0.422

AC:

51004

Asia WGS

AF:

0.341

AC:

1189

AN:

3478

EpiCase

AF:

0.432

EpiControl

AF:

0.427

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 11, 2016

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. -

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: 42% of total chromosomes in ExAC -

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 24, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 66% of patients studied by a panel of primary immunodeficiencies. Number of patients: 63. Only high quality variants are reported. -

not provided

Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Van Maldergem syndrome 2

Benign:1

Aug 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hennekam lymphangiectasia-lymphedema syndrome 2

Benign:1

Aug 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.72

BayesDel_noAF

Benign

-0.66

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.13

Eigen

Benign

0.15

Eigen_PC

Uncertain

0.23

FATHMM_MKL

Uncertain

0.89

LIST_S2

Uncertain

0.93

MetaRNN

Benign

0.00024

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.84

PrimateAI

Uncertain

0.66

PROVEAN

Benign

-1.6

REVEL

Benign

0.12

Sift

Benign

0.20

Sift4G

Uncertain

0.016

Polyphen

0.57

Vest4

0.13

MPC

0.50

ClinPred

0.020

GERP RS

5.1

Varity_R

0.26

gMVP

0.26

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