rs12508222

chr4-125449492-G-Achr4-125449492-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001291303.3(FAT4):c.8482G>A(p.Asp2828Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0141 in 1,613,770 control chromosomes in the GnomAD database, including 1,577 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.028 (232 hom., cov: 32)
  • Exomes 𝑓: 0.013 (1345 hom.)
• Consequence: FAT4 NM_001291303.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 9.71

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=0.003456831).
• BP6: Variant 4-125449492-G-A is Benign according to our data. Variant chr4-125449492-G-A is described in ClinVar as [Benign]. Clinvar id is 380933.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-125449492-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.134 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FAT4	NM_001291303.3	c.8482G>A	p.Asp2828Asn	missense_variant	10/18	ENST00000394329.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FAT4	ENST00000394329.9	c.8482G>A	p.Asp2828Asn	missense_variant	10/18	5	NM_001291303.3	P1
FAT4	ENST00000335110.5	c.3370G>A	p.Asp1124Asn	missense_variant	9/15	1
FAT4	ENST00000674496.2	c.3253G>A	p.Asp1085Asn	missense_variant	9/17

Frequencies

GnomAD3 genomes AF: 0.0280 AC: 4257 AN: 152008 Hom.: 233 Cov.: 32

Gnomad AFR AF: 0.0322

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.128

Gnomad ASJ AF: 0.000289

Gnomad EAS AF: 0.143

Gnomad SAS AF: 0.0315

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000471

Gnomad OTH AF: 0.0258

GnomAD3 exomes AF: 0.0428 AC: 10698 AN: 249844 Hom.: 906 AF XY: 0.0357 AC XY: 4832 AN XY: 135400

Gnomad AFR exome AF: 0.0339

Gnomad AMR exome AF: 0.184

Gnomad ASJ exome AF: 0.000498

Gnomad EAS exome AF: 0.150

Gnomad SAS exome AF: 0.0268

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000389

Gnomad OTH exome AF: 0.0284

GnomAD4 exome AF: 0.0126 AC: 18437 AN: 1461644 Hom.: 1345 Cov.: 41 AF XY: 0.0121 AC XY: 8801 AN XY: 727112

Gnomad4 AFR exome AF: 0.0307

Gnomad4 AMR exome AF: 0.176

Gnomad4 ASJ exome AF: 0.000421

Gnomad4 EAS exome AF: 0.146

Gnomad4 SAS exome AF: 0.0250

Gnomad4 FIN exome AF: 0.000150

Gnomad4 NFE exome AF: 0.000297

Gnomad4 OTH exome AF: 0.0202

GnomAD4 genome AF: 0.0280 AC: 4260 AN: 152126 Hom.: 232 Cov.: 32 AF XY: 0.0305 AC XY: 2270 AN XY: 74366

Gnomad4 AFR AF: 0.0322

Gnomad4 AMR AF: 0.128

Gnomad4 ASJ AF: 0.000289

Gnomad4 EAS AF: 0.142

Gnomad4 SAS AF: 0.0311

Gnomad4 FIN AF: 0.000189

Gnomad4 NFE AF: 0.000471

Gnomad4 OTH AF: 0.0270

Alfa AF: 0.0117 Hom.: 159

Bravo AF: 0.0383

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.0302 AC: 133

ESP6500EA AF: 0.00140 AC: 12

ExAC AF: 0.0360 AC: 4364

EpiCase AF: 0.000600

EpiControl AF: 0.000237

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 21, 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, 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 22% of patients studied by a panel of primary immunodeficiencies. Number of patients: 21. Only high quality variants are reported. -

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
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.61
Cadd	Uncertain	25
Dann	Uncertain	0.99
DEOGEN2	Benign	0.028	T;.
Eigen	Uncertain	0.59
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D;D
MetaRNN	Benign	0.0035	T;T
MetaSVM	Benign	-0.36	T
MutationAssessor	Benign	-0.23	N;.
MutationTaster	Benign	3.3e-8	P;P
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	1.5	N;N
REVEL	Benign	0.22
Sift	Benign	1.0	T;T
Sift4G	Uncertain	0.0070	D;D
Polyphen		0.99	D;D
Vest4		0.49
MPC		0.30
ClinPred		0.045	T
GERP RS		5.6
Varity_R		0.080
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: rs12508222; hg19: chr4-126370647; COSMIC: COSV58678981; COSMIC: COSV58678981;