NM_001291303.3:c.1195delC

Variant names:

• chr4-125317605-TC-T
• rs587777725
• NM_001291303.3:c.1195delC

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_001291303.3(FAT4):​c.1195delC​(p.Leu399SerfsTer19) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FAT4 NM_001291303.3 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 1.70
• 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):

• 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: Pathogenic. The variant received 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 4-125317605-TC-T is Pathogenic according to our data. Variant chr4-125317605-TC-T is described in CliVar as Pathogenic. Clinvar id is 156110.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr4-125317605-TC-T is described in CliVar as Pathogenic. Clinvar id is 156110.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr4-125317605-TC-T is described in CliVar as Pathogenic. Clinvar id is 156110.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr4-125317605-TC-T is described in CliVar as Pathogenic. Clinvar id is 156110.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr4-125317605-TC-T is described in CliVar as Pathogenic. Clinvar id is 156110.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr4-125317605-TC-T is described in CliVar as Pathogenic. Clinvar id is 156110.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr4-125317605-TC-T is described in CliVar as Pathogenic. Clinvar id is 156110.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr4-125317605-TC-T is described in CliVar as Pathogenic. Clinvar id is 156110.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAT4	NM_001291303.3	c.1195delC	p.Leu399SerfsTer19	frameshift_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.1195delC	p.Leu399SerfsTer19	frameshift_variant	Exon 2 of 18	5	NM_001291303.3	ENSP00000377862.4
FAT4	ENST00000674496.2	c.-55+1629delC		intron_variant	Intron 1 of 16			ENSP00000501473.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Hennekam lymphangiectasia-lymphedema syndrome 2 Pathogenic:1

Sep 01, 2014

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.7
Mutation Taster		=11/189	disease causing (ClinVar)

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: rs587777725; hg19: chr4-126238760;