rs35340865

chr4-125491479-C-G

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.14663C>G(p.Ala4888Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00146 in 1,614,118 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0052 (8 hom., cov: 33)
  • Exomes 𝑓: 0.0011 (9 hom.)
• Consequence: FAT4 NM_001291303.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 3.39

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=0.007138908).
• BP6: Variant 4-125491479-C-G is Benign according to our data. Variant chr4-125491479-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 445551.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-125491479-C-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00516 (785/152238) while in subpopulation AFR AF= 0.0157 (651/41530). AF 95% confidence interval is 0.0147. There are 8 homozygotes in gnomad4. There are 372 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FAT4	NM_001291303.3	c.14663C>G	p.Ala4888Gly	missense_variant	18/18	ENST00000394329.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FAT4	ENST00000394329.9	c.14663C>G	p.Ala4888Gly	missense_variant	18/18	5	NM_001291303.3	P1
FAT4	ENST00000335110.5	c.9380C>G	p.Ala3127Gly	missense_variant	15/15	1
FAT4	ENST00000674496.2	c.9434C>G	p.Ala3145Gly	missense_variant	17/17

Frequencies

GnomAD3 genomes AF: 0.00515 AC: 784 AN: 152120 Hom.: 8 Cov.: 33

Gnomad AFR AF: 0.0157

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00406

Gnomad ASJ AF: 0.00634

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000470

Gnomad OTH AF: 0.00765

GnomAD3 exomes AF: 0.00203 AC: 511 AN: 251330 Hom.: 4 AF XY: 0.00179 AC XY: 243 AN XY: 135848

Gnomad AFR exome AF: 0.0158

Gnomad AMR exome AF: 0.00191

Gnomad ASJ exome AF: 0.00953

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000634

Gnomad OTH exome AF: 0.00310

GnomAD4 exome AF: 0.00107 AC: 1569 AN: 1461880 Hom.: 9 Cov.: 33 AF XY: 0.00103 AC XY: 751 AN XY: 727238

Gnomad4 AFR exome AF: 0.0159

Gnomad4 AMR exome AF: 0.00215

Gnomad4 ASJ exome AF: 0.00792

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000474

Gnomad4 OTH exome AF: 0.00305

GnomAD4 genome AF: 0.00516 AC: 785 AN: 152238 Hom.: 8 Cov.: 33 AF XY: 0.00500 AC XY: 372 AN XY: 74442

Gnomad4 AFR AF: 0.0157

Gnomad4 AMR AF: 0.00405

Gnomad4 ASJ AF: 0.00634

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000470

Gnomad4 OTH AF: 0.00757

Alfa AF: 0.00211 Hom.: 3

Bravo AF: 0.00608

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.0152 AC: 67

ESP6500EA AF: 0.000930 AC: 8

ExAC AF: 0.00232 AC: 282

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.000763

EpiControl AF: 0.00113

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 06, 2018	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	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	May 04, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -

FAT4-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 14, 2019

This variant is classified as 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	0.075
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.50
Cadd	Benign	17
Dann	Benign	0.92
DEOGEN2	Benign	0.039	T;.
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.089
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.83	T;T
MetaRNN	Benign	0.0071	T;T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	1.1	L;.
MutationTaster	Benign	0.86	N;N
PrimateAI	Uncertain	0.48	T
PROVEAN	Benign	-0.45	N;N
REVEL	Benign	0.18
Sift	Benign	0.21	T;T
Sift4G	Benign	0.68	T;T
Polyphen		0.0	B;B
Vest4		0.067
MVP		0.14
MPC		0.15
ClinPred		0.011	T
GERP RS		5.2
Varity_R		0.085
gMVP		0.18

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: rs35340865; hg19: chr4-126412634; COSMIC: COSV99060145;