4-125450497-G-C

Variant names:

• chr4-125450497-G-C
• rs370088878
• NM_001291303.3:c.9487G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001291303.3(FAT4):​c.9487G>C​(p.Glu3163Gln) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E3163K) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FAT4 NM_001291303.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.71
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAT4	NM_001291303.3	c.9487G>C	p.Glu3163Gln	missense_variant	Exon 10 of 18	ENST00000394329.9	NP_001278232.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FAT4	ENST00000394329.9	c.9487G>C	p.Glu3163Gln	missense_variant	Exon 10 of 18	5	NM_001291303.3	ENSP00000377862.4
FAT4	ENST00000335110.5	c.4375G>C	p.Glu1459Gln	missense_variant	Exon 9 of 15	1		ENSP00000335169.5
FAT4	ENST00000674496.2	c.4258G>C	p.Glu1420Gln	missense_variant	Exon 9 of 17			ENSP00000501473.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 41

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Aug 15, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.9481G>C (p.E3161Q) alteration is located in exon 9 (coding exon 9) of the FAT4 gene. This alteration results from a G to C substitution at nucleotide position 9481, causing the glutamic acid (E) at amino acid position 3161 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.056	T;.
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.87	D;D
M_CAP	Benign	0.026	D
MetaRNN	Uncertain	0.65	D;D
MetaSVM	Benign	-0.52	T
MutationAssessor	Benign	0.41	N;.
PhyloP100		6.7
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.45	N;N
REVEL	Benign	0.25
Sift	Benign	0.34	T;T
Sift4G	Benign	0.075	T;T
Polyphen		0.95	P;D
Vest4		0.56
MutPred		0.49		Loss of glycosylation at S3165 (P = 0.089);.;
MVP		0.24
MPC		0.54
ClinPred		0.62	D
GERP RS		5.6
Varity_R		0.14
gMVP		0.40
Mutation Taster		=70/30	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: rs370088878; hg19: chr4-126371652;