rs76491994

chr4-125451820-A-Cchr4-125451820-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001291303.3(FAT4):c.10810A>C(p.Ile3604Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0138 in 1,614,138 control chromosomes in the GnomAD database, including 221 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.010 (16 hom., cov: 32)
  • Exomes 𝑓: 0.014 (205 hom.)
• Consequence: FAT4 NM_001291303.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 2.97

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=0.0034600794).
• BP6: Variant 4-125451820-A-C is Benign according to our data. Variant chr4-125451820-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 377311.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-125451820-A-C is described in Lovd as [Benign]. Variant chr4-125451820-A-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00999 (1522/152288) while in subpopulation EAS AF= 0.0276 (143/5178). AF 95% confidence interval is 0.0239. There are 16 homozygotes in gnomad4. There are 745 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 16 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FAT4	NM_001291303.3	c.10810A>C	p.Ile3604Leu	missense_variant	10/18	ENST00000394329.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FAT4	ENST00000394329.9	c.10810A>C	p.Ile3604Leu	missense_variant	10/18	5	NM_001291303.3	P1
FAT4	ENST00000335110.5	c.5698A>C	p.Ile1900Leu	missense_variant	9/15	1
FAT4	ENST00000674496.2	c.5581A>C	p.Ile1861Leu	missense_variant	9/17

Frequencies

GnomAD3 genomes AF: 0.00998 AC: 1519 AN: 152170 Hom.: 16 Cov.: 32

Gnomad AFR AF: 0.00258

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00982

Gnomad ASJ AF: 0.00230

Gnomad EAS AF: 0.0279

Gnomad SAS AF: 0.00705

Gnomad FIN AF: 0.0154

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0132

Gnomad OTH AF: 0.00765

GnomAD3 exomes AF: 0.0120 AC: 3013 AN: 250644 Hom.: 31 AF XY: 0.0119 AC XY: 1610 AN XY: 135396

Gnomad AFR exome AF: 0.00240

Gnomad AMR exome AF: 0.0103

Gnomad ASJ exome AF: 0.00149

Gnomad EAS exome AF: 0.0299

Gnomad SAS exome AF: 0.00581

Gnomad FIN exome AF: 0.0168

Gnomad NFE exome AF: 0.0128

Gnomad OTH exome AF: 0.0108

GnomAD4 exome AF: 0.0142 AC: 20814 AN: 1461850 Hom.: 205 Cov.: 71 AF XY: 0.0140 AC XY: 10180 AN XY: 727230

Gnomad4 AFR exome AF: 0.00203

Gnomad4 AMR exome AF: 0.0101

Gnomad4 ASJ exome AF: 0.00184

Gnomad4 EAS exome AF: 0.0206

Gnomad4 SAS exome AF: 0.00657

Gnomad4 FIN exome AF: 0.0168

Gnomad4 NFE exome AF: 0.0155

Gnomad4 OTH exome AF: 0.0112

GnomAD4 genome AF: 0.00999 AC: 1522 AN: 152288 Hom.: 16 Cov.: 32 AF XY: 0.0100 AC XY: 745 AN XY: 74464

Gnomad4 AFR AF: 0.00257

Gnomad4 AMR AF: 0.0101

Gnomad4 ASJ AF: 0.00230

Gnomad4 EAS AF: 0.0276

Gnomad4 SAS AF: 0.00726

Gnomad4 FIN AF: 0.0154

Gnomad4 NFE AF: 0.0132

Gnomad4 OTH AF: 0.00757

Alfa AF: 0.0131 Hom.: 26

Bravo AF: 0.00918

TwinsUK AF: 0.0183 AC: 68

ALSPAC AF: 0.0161 AC: 62

ESP6500AA AF: 0.00409 AC: 18

ESP6500EA AF: 0.0140 AC: 120

ExAC AF: 0.0112 AC: 1357

Asia WGS AF: 0.0120 AC: 41 AN: 3478

EpiCase AF: 0.0126

EpiControl AF: 0.0132

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 04, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	FAT4: BP4, BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 28, 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, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely 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: 3% of E. Asian chromosomes in ExAC -

Van Maldergem syndrome 2;C4014939:Hennekam lymphangiectasia-lymphedema syndrome 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 25, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.46
Cadd	Benign	19
Dann	Benign	0.95
DEOGEN2	Benign	0.16	T;.
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.67
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.88	D;D
MetaRNN	Benign	0.0035	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.2	M;.
MutationTaster	Benign	0.98	D;D
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.9	N;N
REVEL	Benign	0.064
Sift	Uncertain	0.010	D;D
Sift4G	Uncertain	0.014	D;D
Polyphen		0.27	B;B
Vest4		0.22
MPC		0.41
ClinPred		0.011	T
GERP RS		0.80
Varity_R		0.32
gMVP		0.45

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: rs76491994; hg19: chr4-126372975; COSMIC: COSV58691157; COSMIC: COSV58691157;