rs2710555

chr4-125320716-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001291303.3(FAT4):c.4305C>T(p.Ile1435=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.704 in 1,613,428 control chromosomes in the GnomAD database, including 403,225 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.73 (41728 hom., cov: 33)
  • Exomes 𝑓: 0.70 (361497 hom.)
• Consequence: FAT4 NM_001291303.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.852

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.32).
• BP6: Variant 4-125320716-C-T is Benign according to our data. Variant chr4-125320716-C-T is described in ClinVar as [Benign]. Clinvar id is 377855.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-125320716-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.852 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.849 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FAT4	NM_001291303.3	c.4305C>T	p.Ile1435=	synonymous_variant	2/18	ENST00000394329.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FAT4	ENST00000394329.9	c.4305C>T	p.Ile1435=	synonymous_variant	2/18	5	NM_001291303.3	P1
FAT4	ENST00000674496.2	c.-55+4739C>T		intron_variant
FAT4	ENST00000678072.1	n.1911C>T		non_coding_transcript_exon_variant	1/2

Frequencies

GnomAD3 genomes AF: 0.734 AC: 111548 AN: 152058 Hom.: 41663 Cov.: 33

Gnomad AFR AF: 0.856

Gnomad AMI AF: 0.696

Gnomad AMR AF: 0.727

Gnomad ASJ AF: 0.731

Gnomad EAS AF: 0.462

Gnomad SAS AF: 0.728

Gnomad FIN AF: 0.573

Gnomad MID AF: 0.688

Gnomad NFE AF: 0.707

Gnomad OTH AF: 0.731

GnomAD3 exomes AF: 0.691 AC: 172243 AN: 249316 Hom.: 60491 AF XY: 0.692 AC XY: 93656 AN XY: 135268

Gnomad AFR exome AF: 0.861

Gnomad AMR exome AF: 0.697

Gnomad ASJ exome AF: 0.731

Gnomad EAS exome AF: 0.454

Gnomad SAS exome AF: 0.751

Gnomad FIN exome AF: 0.575

Gnomad NFE exome AF: 0.705

Gnomad OTH exome AF: 0.689

GnomAD4 exome AF: 0.701 AC: 1024607 AN: 1461252 Hom.: 361497 Cov.: 48 AF XY: 0.702 AC XY: 510616 AN XY: 726978

Gnomad4 AFR exome AF: 0.865

Gnomad4 AMR exome AF: 0.700

Gnomad4 ASJ exome AF: 0.735

Gnomad4 EAS exome AF: 0.468

Gnomad4 SAS exome AF: 0.747

Gnomad4 FIN exome AF: 0.581

Gnomad4 NFE exome AF: 0.706

Gnomad4 OTH exome AF: 0.702

GnomAD4 genome AF: 0.734 AC: 111672 AN: 152176 Hom.: 41728 Cov.: 33 AF XY: 0.726 AC XY: 53989 AN XY: 74360

Gnomad4 AFR AF: 0.856

Gnomad4 AMR AF: 0.726

Gnomad4 ASJ AF: 0.731

Gnomad4 EAS AF: 0.461

Gnomad4 SAS AF: 0.729

Gnomad4 FIN AF: 0.573

Gnomad4 NFE AF: 0.707

Gnomad4 OTH AF: 0.733

Alfa AF: 0.718 Hom.: 53925

Bravo AF: 0.744

Asia WGS AF: 0.663 AC: 2309 AN: 3478

EpiCase AF: 0.706

EpiControl AF: 0.706

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 08, 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 DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
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: 70% 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 95% of patients studied by a panel of primary immunodeficiencies. Number of patients: 90. Only high quality variants are reported. -

Van Maldergem syndrome 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 10, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Hennekam lymphangiectasia-lymphedema syndrome 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.32
Cadd	Benign	6.5
Dann	Benign	0.71

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: rs2710555; hg19: chr4-126241871; COSMIC: COSV67882328;