rs72928772

Positions:

• chr4-125316816-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001291303.3(FAT4):​c.405C>T​(p.Phe135=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.209 in 1,613,560 control chromosomes in the GnomAD database, including 36,566 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (2631 hom., cov: 32)
  • Exomes 𝑓: 0.21 (33935 hom.)
• Consequence: FAT4 NM_001291303.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 2.37

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=-0.48).
• BP6: Variant 4-125316816-C-T is Benign according to our data. Variant chr4-125316816-C-T is described in ClinVar as [Benign]. Clinvar id is 380815.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-125316816-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=2.37 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.223 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FAT4	NM_001291303.3	c.405C>T	p.Phe135=	synonymous_variant	2/18	ENST00000394329.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FAT4	ENST00000394329.9	c.405C>T	p.Phe135=	synonymous_variant	2/18	5	NM_001291303.3	P1
FAT4	ENST00000674496.2	c.-55+839C>T		intron_variant

Frequencies

GnomAD3 genomes AF: 0.174 AC: 26505 AN: 152028 Hom.: 2630 Cov.: 32

Gnomad AFR AF: 0.0876

Gnomad AMI AF: 0.264

Gnomad AMR AF: 0.150

Gnomad ASJ AF: 0.203

Gnomad EAS AF: 0.112

Gnomad SAS AF: 0.161

Gnomad FIN AF: 0.238

Gnomad MID AF: 0.142

Gnomad NFE AF: 0.226

Gnomad OTH AF: 0.179

GnomAD3 exomes AF: 0.185 AC: 46000 AN: 248304 Hom.: 4500 AF XY: 0.189 AC XY: 25467 AN XY: 134796

Gnomad AFR exome AF: 0.0852

Gnomad AMR exome AF: 0.124

Gnomad ASJ exome AF: 0.210

Gnomad EAS exome AF: 0.116

Gnomad SAS exome AF: 0.167

Gnomad FIN exome AF: 0.226

Gnomad NFE exome AF: 0.223

Gnomad OTH exome AF: 0.201

GnomAD4 exome AF: 0.212 AC: 310007 AN: 1461414 Hom.: 33935 Cov.: 35 AF XY: 0.211 AC XY: 153756 AN XY: 726984

Gnomad4 AFR exome AF: 0.0806

Gnomad4 AMR exome AF: 0.126

Gnomad4 ASJ exome AF: 0.213

Gnomad4 EAS exome AF: 0.107

Gnomad4 SAS exome AF: 0.169

Gnomad4 FIN exome AF: 0.225

Gnomad4 NFE exome AF: 0.227

Gnomad4 OTH exome AF: 0.195

GnomAD4 genome AF: 0.174 AC: 26508 AN: 152146 Hom.: 2631 Cov.: 32 AF XY: 0.174 AC XY: 12907 AN XY: 74364

Gnomad4 AFR AF: 0.0876

Gnomad4 AMR AF: 0.150

Gnomad4 ASJ AF: 0.203

Gnomad4 EAS AF: 0.112

Gnomad4 SAS AF: 0.161

Gnomad4 FIN AF: 0.238

Gnomad4 NFE AF: 0.226

Gnomad4 OTH AF: 0.176

Alfa AF: 0.203 Hom.: 1475

Bravo AF: 0.162

Asia WGS AF: 0.140 AC: 489 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 14, 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, 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: 19% of total chromosomes in ExAC -
Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jan 24, 2024	This variant is classified as Benign based on local population frequency. This variant was detected in 34% of patients studied by a panel of primary immunodeficiencies. Number of patients: 32. Only high quality variants are reported. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	12
DANN	Benign	0.91

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: rs72928772; hg19: chr4-126237971; COSMIC: COSV67886260;