rs78040862

Positions:

• chr4-125487377-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001291303.3(FAT4):​c.12855T>C​(p.Asp4285=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00487 in 1,613,850 control chromosomes in the GnomAD database, including 31 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0036 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0050 (31 hom.)
• Consequence: FAT4 NM_001291303.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 1.22

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 4-125487377-T-C is Benign according to our data. Variant chr4-125487377-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 380888.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-125487377-T-C is described in Lovd as [Likely_benign]. Variant chr4-125487377-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=1.22 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00363 (553/152338) while in subpopulation NFE AF= 0.00554 (377/68034). AF 95% confidence interval is 0.00508. There are 0 homozygotes in gnomad4. There are 250 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 31 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FAT4	NM_001291303.3	c.12855T>C	p.Asp4285=	synonymous_variant	17/18	ENST00000394329.9	NP_001278232.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FAT4	ENST00000394329.9	c.12855T>C	p.Asp4285=	synonymous_variant	17/18	5	NM_001291303.3	ENSP00000377862	P1
FAT4	ENST00000335110.5	c.7572T>C	p.Asp2524=	synonymous_variant	14/15	1		ENSP00000335169
FAT4	ENST00000674496.2	c.7626T>C	p.Asp2542=	synonymous_variant	16/17			ENSP00000501473

Frequencies

GnomAD3 genomes AF: 0.00363 AC: 552 AN: 152220 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000869

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00288

Gnomad ASJ AF: 0.0147

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00290

Gnomad FIN AF: 0.00122

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00554

Gnomad OTH AF: 0.00621

GnomAD3 exomes AF: 0.00495 AC: 1241 AN: 250696 Hom.: 9 AF XY: 0.00537 AC XY: 728 AN XY: 135626

Gnomad AFR exome AF: 0.000812

Gnomad AMR exome AF: 0.00318

Gnomad ASJ exome AF: 0.0185

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00435

Gnomad FIN exome AF: 0.00157

Gnomad NFE exome AF: 0.00637

Gnomad OTH exome AF: 0.00689

GnomAD4 exome AF: 0.00500 AC: 7308 AN: 1461512 Hom.: 31 Cov.: 31 AF XY: 0.00513 AC XY: 3727 AN XY: 727020

Gnomad4 AFR exome AF: 0.000866

Gnomad4 AMR exome AF: 0.00322

Gnomad4 ASJ exome AF: 0.0171

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00398

Gnomad4 FIN exome AF: 0.00174

Gnomad4 NFE exome AF: 0.00524

Gnomad4 OTH exome AF: 0.00528

GnomAD4 genome AF: 0.00363 AC: 553 AN: 152338 Hom.: 0 Cov.: 32 AF XY: 0.00336 AC XY: 250 AN XY: 74498

Gnomad4 AFR AF: 0.000866

Gnomad4 AMR AF: 0.00288

Gnomad4 ASJ AF: 0.0147

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00311

Gnomad4 FIN AF: 0.00122

Gnomad4 NFE AF: 0.00554

Gnomad4 OTH AF: 0.00615

Alfa AF: 0.00656 Hom.: 4

Bravo AF: 0.00408

Asia WGS AF: 0.00375 AC: 13 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 07, 2023	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	FAT4: BP4, BP7, BS2 -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 05, 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. -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 05, 2018	- -

FAT4-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 15, 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
BayesDel_noAF	Benign	-0.52
CADD	Benign	3.7
DANN	Benign	0.58

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: rs78040862; hg19: chr4-126408532;