rs140055438

chr4-125414950-A-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001291303.3(FAT4):c.5987A>G(p.Lys1996Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00113 in 1,613,814 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 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 0.0024 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0010 (6 hom.)
• Consequence: FAT4 NM_001291303.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7
• Conservation: PhyloP100: 1.35

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0068081915).
• BP6: Variant 4-125414950-A-G is Benign according to our data. Variant chr4-125414950-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 435175.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Uncertain_significance=1}. Variant chr4-125414950-A-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00239 (364/152254) while in subpopulation AMR AF= 0.00805 (123/15286). AF 95% confidence interval is 0.00689. There are 4 homozygotes in gnomad4. There are 181 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FAT4	NM_001291303.3	c.5987A>G	p.Lys1996Arg	missense_variant	6/18	ENST00000394329.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FAT4	ENST00000394329.9	c.5987A>G	p.Lys1996Arg	missense_variant	6/18	5	NM_001291303.3	P1
FAT4	ENST00000335110.5	c.881A>G	p.Lys294Arg	missense_variant	5/15	1
FAT4	ENST00000674496.2	c.758A>G	p.Lys253Arg	missense_variant	5/17

Frequencies

GnomAD3 genomes AF: 0.00239 AC: 364 AN: 152136 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00340

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00806

Gnomad ASJ AF: 0.000867

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00118

Gnomad OTH AF: 0.00669

GnomAD3 exomes AF: 0.00146 AC: 366 AN: 251014 Hom.: 3 AF XY: 0.00125 AC XY: 170 AN XY: 135632

Gnomad AFR exome AF: 0.00357

Gnomad AMR exome AF: 0.00382

Gnomad ASJ exome AF: 0.00209

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00116

Gnomad OTH exome AF: 0.00343

GnomAD4 exome AF: 0.00100 AC: 1465 AN: 1461560 Hom.: 6 Cov.: 33 AF XY: 0.000967 AC XY: 703 AN XY: 727044

Gnomad4 AFR exome AF: 0.00320

Gnomad4 AMR exome AF: 0.00387

Gnomad4 ASJ exome AF: 0.00145

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000812

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000871

Gnomad4 OTH exome AF: 0.00227

GnomAD4 genome AF: 0.00239 AC: 364 AN: 152254 Hom.: 4 Cov.: 32 AF XY: 0.00243 AC XY: 181 AN XY: 74442

Gnomad4 AFR AF: 0.00339

Gnomad4 AMR AF: 0.00805

Gnomad4 ASJ AF: 0.000867

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00118

Gnomad4 OTH AF: 0.00662

Alfa AF: 0.00105 Hom.: 1

Bravo AF: 0.00300

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.00386 AC: 17

ESP6500EA AF: 0.000930 AC: 8

ExAC AF: 0.00118 AC: 143

EpiCase AF: 0.00169

EpiControl AF: 0.00166

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:5

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 23, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	FAT4: BP4, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 26, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Sep 14, 2016

- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 25, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

FAT4-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 09, 2020

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	0.068
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.65
Cadd	Benign	13
Dann	Uncertain	0.99
DEOGEN2	Benign	0.071	T;.
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.68
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.54	T;T
M_CAP	Benign	0.0076	T
MetaRNN	Benign	0.0068	T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.14	N;.
MutationTaster	Benign	0.57	N;N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.1	N;N
REVEL	Benign	0.064
Sift	Benign	0.29	T;T
Sift4G	Uncertain	0.034	D;D
Polyphen		0.93	P;B
Vest4		0.053
MVP		0.19
MPC		0.17
ClinPred		0.0087	T
GERP RS		2.9
Varity_R		0.023
gMVP		0.21

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: rs140055438; hg19: chr4-126336105;