4-125317769-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001291303.3(FAT4):c.1358A>T(p.Gln453Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.438 in 1,613,882 control chromosomes in the GnomAD database, including 157,747 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q453P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.46 (16452 hom., cov: 32)
  • Exomes 𝑓: 0.44 (141295 hom.)
• Consequence: FAT4 NM_001291303.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.151

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=2.3591885E-5).
• BP6: Variant 4-125317769-A-T is Benign according to our data. Variant chr4-125317769-A-T is described in ClinVar as [Benign]. Clinvar id is 380812.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-125317769-A-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.56 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FAT4	NM_001291303.3	c.1358A>T	p.Gln453Leu	missense_variant	2/18	ENST00000394329.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FAT4	ENST00000394329.9	c.1358A>T	p.Gln453Leu	missense_variant	2/18	5	NM_001291303.3	P1
FAT4	ENST00000674496.2	c.-55+1792A>T		intron_variant

Frequencies

GnomAD3 genomes AF: 0.459 AC: 69802 AN: 151946 Hom.: 16426 Cov.: 32

Gnomad AFR AF: 0.566

Gnomad AMI AF: 0.467

Gnomad AMR AF: 0.403

Gnomad ASJ AF: 0.353

Gnomad EAS AF: 0.254

Gnomad SAS AF: 0.385

Gnomad FIN AF: 0.390

Gnomad MID AF: 0.326

Gnomad NFE AF: 0.445

Gnomad OTH AF: 0.439

GnomAD3 exomes AF: 0.414 AC: 103306 AN: 249260 Hom.: 22139 AF XY: 0.413 AC XY: 55854 AN XY: 135286

Gnomad AFR exome AF: 0.573

Gnomad AMR exome AF: 0.377

Gnomad ASJ exome AF: 0.365

Gnomad EAS exome AF: 0.245

Gnomad SAS exome AF: 0.406

Gnomad FIN exome AF: 0.384

Gnomad NFE exome AF: 0.444

Gnomad OTH exome AF: 0.411

GnomAD4 exome AF: 0.436 AC: 637658 AN: 1461818 Hom.: 141295 Cov.: 71 AF XY: 0.434 AC XY: 315813 AN XY: 727204

Gnomad4 AFR exome AF: 0.576

Gnomad4 AMR exome AF: 0.381

Gnomad4 ASJ exome AF: 0.364

Gnomad4 EAS exome AF: 0.255

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: 69882 AN: 152064 Hom.: 16452 Cov.: 32 AF XY: 0.454 AC XY: 33731 AN XY: 74318

Gnomad4 AFR AF: 0.567

Gnomad4 AMR AF: 0.402

Gnomad4 ASJ AF: 0.353

Gnomad4 EAS AF: 0.254

Gnomad4 SAS AF: 0.386

Gnomad4 FIN AF: 0.390

Gnomad4 NFE AF: 0.445

Gnomad4 OTH AF: 0.434

Alfa AF: 0.400 Hom.: 3650

Bravo AF: 0.464

TwinsUK AF: 0.462 AC: 1714

ALSPAC AF: 0.441 AC: 1699

ESP6500AA AF: 0.545 AC: 2215

ESP6500EA AF: 0.427 AC: 3559

ExAC AF: 0.423 AC: 51126

Asia WGS AF: 0.343 AC: 1198 AN: 3478

EpiCase AF: 0.432

EpiControl AF: 0.427

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jan 24, 2024	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. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 11, 2016	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. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	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 -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Van Maldergem syndrome 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 10, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Hennekam lymphangiectasia-lymphedema syndrome 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.67
Cadd	Benign	9.6
Dann	Benign	0.82
DEOGEN2	Benign	0.046	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.27	N
LIST_S2	Benign	0.67	T
MetaRNN	Benign	0.000024	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.28	N
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.31	N
REVEL	Benign	0.018
Sift	Benign	0.33	T
Sift4G	Benign	0.22	T
Polyphen		0.0020	B
Vest4		0.081
MPC		0.15
ClinPred		0.0027	T
GERP RS		-2.6
Varity_R		0.092
gMVP		0.28

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

Other links and lift over

dbSNP: rs6847454; hg19: chr4-126238924; COSMIC: COSV67886468;