rs148918820

chr4-125449088-C-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BS1_Supporting

The NM_001291303.3(FAT4):c.8078C>T(p.Ser2693Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000639 in 1,613,816 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00025 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00068 (0 hom.)
• Consequence: FAT4 NM_001291303.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: 3.98

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 Likely_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20259643).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00025 (38/152110) while in subpopulation NFE AF= 0.000456 (31/68000). AF 95% confidence interval is 0.00033. There are 0 homozygotes in gnomad4. There are 15 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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FAT4	NM_001291303.3	c.8078C>T	p.Ser2693Leu	missense_variant	10/18	ENST00000394329.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FAT4	ENST00000394329.9	c.8078C>T	p.Ser2693Leu	missense_variant	10/18	5	NM_001291303.3	P1
FAT4	ENST00000335110.5	c.2966C>T	p.Ser989Leu	missense_variant	9/15	1
FAT4	ENST00000674496.2	c.2849C>T	p.Ser950Leu	missense_variant	9/17

Frequencies

GnomAD3 genomes AF: 0.000250 AC: 38 AN: 151992 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000456

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000168 AC: 42 AN: 250442 Hom.: 0 AF XY: 0.000155 AC XY: 21 AN XY: 135676

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000371

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000679 AC: 993 AN: 1461706 Hom.: 0 Cov.: 40 AF XY: 0.000627 AC XY: 456 AN XY: 727148

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000870

Gnomad4 OTH exome AF: 0.000248

GnomAD4 genome AF: 0.000250 AC: 38 AN: 152110 Hom.: 0 Cov.: 32 AF XY: 0.000202 AC XY: 15 AN XY: 74346

Gnomad4 AFR AF: 0.0000964

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000456

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000425 Hom.: 0

Bravo AF: 0.000317

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000189 AC: 23

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000491

EpiControl AF: 0.000533

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Aug 16, 2022	This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 2691 of the FAT4 protein (p.Ser2691Leu). This variant is present in population databases (rs148918820, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with FAT4-related conditions. ClinVar contains an entry for this variant (Variation ID: 429367). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt FAT4 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 21, 2023	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Dec 09, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.45
Cadd	Benign	21
Dann	Uncertain	0.99
DEOGEN2	Benign	0.31	T;.
Eigen	Benign	-0.051
Eigen_PC	Benign	-0.030
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.83	T;D
M_CAP	Benign	0.050	D
MetaRNN	Benign	0.20	T;T
MetaSVM	Benign	-0.48	T
MutationAssessor	Benign	0.47	N;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.40	T
PROVEAN	Uncertain	-3.1	D;D
REVEL	Benign	0.14
Sift	Benign	0.072	T;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		0.84	P;P
Vest4		0.17
MVP		0.10
MPC		0.38
ClinPred		0.14	T
GERP RS		5.1
Varity_R		0.13
gMVP		0.57

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: rs148918820; hg19: chr4-126370243; COSMIC: COSV58715958; COSMIC: COSV58715958;