chr4-125316542-A-C

Position:

chr4-125316542-A-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS1

The NM_001291303.3(FAT4):c.131A>C(p.Glu44Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000449 in 1,613,986 control chromosomes in the GnomAD database, including 2 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00051 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00044 ( 1 hom. )

Consequence

FAT4
NM_001291303.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3

Conservation

PhyloP100: 2.87

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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008679718).

BP6

Variant 4-125316542-A-C is Benign according to our data. Variant chr4-125316542-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 221921.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1}.

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000506 (77/152224) while in subpopulation AMR AF= 0.00105 (16/15302). AF 95% confidence interval is 0.000656. There are 1 homozygotes in gnomad4. There are 39 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FAT4	NM_001291303.3 linkuse as main transcript	c.131A>C	p.Glu44Ala	missense_variant	2/18	ENST00000394329.9	NP_001278232.1	Q6V0I7A0A6Q8JR05X2G5I7B3KU84

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FAT4	ENST00000394329.9 linkuse as main transcript	c.131A>C	p.Glu44Ala	missense_variant	2/18	5	NM_001291303.3	ENSP00000377862.4		A0A6Q8JR05
FAT4	ENST00000674496.2 linkuse as main transcript	c.-55+565A>C		intron_variant				ENSP00000501473.2		A0A7P0T1I0

Frequencies

GnomAD3 genomes

AF:

0.000506

AC:

AN:

152106

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000725

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00105

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00151

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000544

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000506

AC:

126

AN:

249212

Hom.:

AF XY:

0.000547

AC XY:

AN XY:

135318

show subpopulations

Gnomad AFR exome

AF:

0.000130

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.000894

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00137

Gnomad FIN exome

AF:

0.00107

Gnomad NFE exome

AF:

0.000380

Gnomad OTH exome

AF:

0.000495

GnomAD4 exome

AF:

0.000443

AC:

648

AN:

1461762

Hom.:

Cov.:

AF XY:

0.000469

AC XY:

341

AN XY:

727196

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000112

Gnomad4 ASJ exome

AF:

0.00126

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00111

Gnomad4 FIN exome

AF:

0.000732

Gnomad4 NFE exome

AF:

0.000404

Gnomad4 OTH exome

AF:

0.000315

GnomAD4 genome

AF:

0.000506

AC:

AN:

152224

Hom.:

Cov.:

AF XY:

0.000524

AC XY:

AN XY:

74422

show subpopulations

Gnomad4 AFR

AF:

0.0000722

Gnomad4 AMR

AF:

0.00105

Gnomad4 ASJ

AF:

0.00144

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00151

Gnomad4 NFE

AF:

0.000544

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000256

Hom.:

Bravo

AF:

0.000491

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000364

AC:

ExAC

AF:

0.000513

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.000491

EpiControl

AF:

0.000771

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Feb 02, 2022	Identified with a second variant in the FAT4 gene in addition to a variant in the DAB1 gene in a patient with ocular developmental anomalies in published literature (Chassaing et al., 2016); however, the variant was also seen in both asymptomatic parents and not believed to be the causative variant for that patient; In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26893459) -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 20, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2023	FAT4: BP4 -

Irido-corneo-trabecular dysgenesis;C5680330:Anophthalmia-microphthalmia syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Paul Sabatier University EA-4555, Paul Sabatier University

Jan 01, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.35

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.15

Eigen

Benign

-0.67

Eigen_PC

Benign

-0.50

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.78

M_CAP

Benign

0.023

MetaRNN

Benign

0.0087

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.69

PrimateAI

Benign

0.43

PROVEAN

Benign

-1.6

REVEL

Benign

0.12

Sift

Benign

0.089

Sift4G

Uncertain

0.028

Polyphen

0.0010

Vest4

0.15

MVP

0.45

MPC

0.16

ClinPred

0.0084

GERP RS

3.7

Varity_R

0.067

gMVP

0.29

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