rs1553958385

Variant names:

• chr4-125317324-A-T
• rs1553958385
• NM_001291303.3:c.913A>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001291303.3(FAT4):​c.913A>T​(p.Ile305Phe) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 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. I305T) 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: 4.58
• 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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.903

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAT4	NM_001291303.3	c.913A>T	p.Ile305Phe	missense_variant	Exon 2 of 18	ENST00000394329.9	NP_001278232.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FAT4	ENST00000394329.9	c.913A>T	p.Ile305Phe	missense_variant	Exon 2 of 18	5	NM_001291303.3	ENSP00000377862.4
FAT4	ENST00000674496.2	c.-55+1347A>T		intron_variant	Intron 1 of 16			ENSP00000501473.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hennekam lymphangiectasia-lymphedema syndrome 1 Uncertain:1

Dec 18, 2017

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.60
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Pathogenic	26
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.58	D
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.80	T
M_CAP	Uncertain	0.23	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Uncertain	0.42	D
MutationAssessor	Pathogenic	3.2	M
PhyloP100		4.6
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-3.2	D
REVEL	Uncertain	0.57
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.99	D
Vest4		0.77
MutPred		0.67		Gain of glycosylation at T306 (P = 0.0245);
MVP		0.56
MPC		0.77
ClinPred		0.98	D
GERP RS		5.2
Varity_R		0.54
gMVP		0.76
Mutation Taster		=55/45	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: rs1553958385; hg19: chr4-126238479;