4-125491482-G-A

Variant names:

• chr4-125491482-G-A
• rs35845544
• NM_001291303.3:c.14666G>A

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS1

The NM_001291303.3(FAT4):​c.14666G>A​(p.Arg4889Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000475 in 1,614,162 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R4889S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0024 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00027 (1 hom.)
• Consequence: FAT4 NM_001291303.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 9.39
• Publications: 6 publications found

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]

FAT4 Gene-Disease associations (from GenCC):

• Hennekam lymphangiectasia-lymphedema syndrome 2

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• van Maldergem syndrome 2

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
• multiple congenital anomalies/dysmorphic syndrome-intellectual disability

  Inheritance: AR Classification: STRONG Submitted by: Ambry Genetics
• Hennekam syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• van Maldergem syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008187979).
• BP6: Variant 4-125491482-G-A is Benign according to our data. Variant chr4-125491482-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 445868.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00244 (372/152286) while in subpopulation AFR AF = 0.00828 (344/41560). AF 95% confidence interval is 0.00756. There are 0 homozygotes in GnomAd4. There are 169 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001291303.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FAT4	NM_001291303.3	MANE Select	c.14666G>A	p.Arg4889Lys	missense	Exon 18 of 18	NP_001278232.1
	FAT4	NM_001438396.1		c.14666G>A	p.Arg4889Lys	missense	Exon 17 of 17	NP_001425325.1
	FAT4	NM_001291285.3		c.14663G>A	p.Arg4888Lys	missense	Exon 18 of 18	NP_001278214.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FAT4	ENST00000394329.9	TSL:5 MANE Select	c.14666G>A	p.Arg4889Lys	missense	Exon 18 of 18	ENSP00000377862.4
	FAT4	ENST00000335110.5	TSL:1	c.9383G>A	p.Arg3128Lys	missense	Exon 15 of 15	ENSP00000335169.5
	FAT4	ENST00000674496.2		c.9437G>A	p.Arg3146Lys	missense	Exon 17 of 17	ENSP00000501473.2

Frequencies

GnomAD3 genomes AF: 0.00244 AC: 372 AN: 152168 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00830

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00151

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000764 AC: 192 AN: 251332 AF XY: 0.000523

Gnomad AFR exome AF: 0.00942

Gnomad AMR exome AF: 0.000694

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000968

Gnomad OTH exome AF: 0.000652

GnomAD4 exome AF: 0.000270 AC: 395 AN: 1461876 Hom.: 1 Cov.: 33 AF XY: 0.000237 AC XY: 172 AN XY: 727236

African (AFR) AF: 0.00854 AC: 286 AN: 33480

American (AMR) AF: 0.000894 AC: 40 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5768

European-Non Finnish (NFE) AF: 0.0000297 AC: 33 AN: 1112006

Other (OTH) AF: 0.000513 AC: 31 AN: 60396

GnomAD4 genome AF: 0.00244 AC: 372 AN: 152286 Hom.: 0 Cov.: 33 AF XY: 0.00227 AC XY: 169 AN XY: 74470

African (AFR) AF: 0.00828 AC: 344 AN: 41560

American (AMR) AF: 0.00150 AC: 23 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68016

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000934 Hom.: 1

Bravo AF: 0.00267

ESP6500AA AF: 0.00817 AC: 36

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000964 AC: 117

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Jun 19, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 19, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 28, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:1

Feb 06, 2017

Eurofins Ntd Llc (ga)

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

FAT4-related disorder Benign:1

May 26, 2023

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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 v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Uncertain	0.0
CADD	Benign	20
DANN	Benign	0.33
DEOGEN2	Benign	0.066	T
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.86	D
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.0082	T
MetaSVM	Benign	-0.41	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		9.4
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-0.17	N
REVEL	Uncertain	0.30
Sift	Benign	0.41	T
Sift4G	Pathogenic	0.0	D
Polyphen		0.98	D
Vest4		0.56
MVP		0.67
MPC		0.25
ClinPred		0.10	T
GERP RS		5.2
Varity_R		0.13
gMVP		0.31
Mutation Taster		=53/47	polymorphism

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

Other links and lift over

dbSNP: rs35845544; hg19: chr4-126412637; COSMIC: COSV100627413;