rs587777726

Variant names:

• chr4-125446297-A-C
• rs587777726
• NM_001291303.3:c.7204A>C
• FAT4 p.Arg2402Arg

Your query was ambiguous. Multiple possible variants found:

• chr4-125446297-A-C
• chr4-125446297-A-G

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PVS1_Moderate PM2 PP5

The NM_024582.6(FAT4):​c.7200-2A>C variant causes a splice acceptor, intron 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 Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: FAT4 NM_024582.6 splice_acceptor, intron
• Scores: Splicing: ADA: 0.9997
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 5.65
• Publications: 1 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):

• FAT4-related neurodevelopmental disorder

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• 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 5 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.016392346 fraction of the gene. Cryptic splice site detected, with MaxEntScore 9, offset of -6, new splice context is: atttctgctttctgctttAGtta. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 4-125446297-A-C is Pathogenic according to our data. Variant chr4-125446297-A-C is described in ClinVar as Pathogenic. ClinVar VariationId is 156112.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024582.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FAT4	NM_001291303.3	MANE Select	c.7204A>C	p.Arg2402Arg	synonymous	Exon 9 of 18	NP_001278232.1	A0A6Q8JR05
	FAT4	NM_001438396.1		c.7204A>C	p.Arg2402Arg	synonymous	Exon 8 of 17	NP_001425325.1
	FAT4	NM_001291285.3		c.7204A>C	p.Arg2402Arg	synonymous	Exon 9 of 18	NP_001278214.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FAT4	ENST00000394329.9	TSL:5 MANE Select	c.7204A>C	p.Arg2402Arg	synonymous	Exon 9 of 18	ENSP00000377862.4	A0A6Q8JR05
	FAT4	ENST00000335110.5	TSL:1	c.2094-2A>C		splice_acceptor intron	N/A	ENSP00000335169.5	Q6V0I7-2
	FAT4	ENST00000674496.2		c.1975A>C	p.Arg659Arg	synonymous	Exon 8 of 17	ENSP00000501473.2	A0A7P0T1I0

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Hennekam lymphangiectasia-lymphedema syndrome 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Benign	-0.17
CADD	Benign	15
DANN	Benign	0.85
Eigen	Pathogenic	0.72
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Pathogenic	0.98	D
PhyloP100		5.7
Mutation Taster		=7/93	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
SpliceAI score (max)		0.22		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.22		Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs587777726;

hg19: chr4-126367452;