rs587777724
Variant summary
Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PM4PP3PP5
The NM_001291303.3(FAT4):c.7041_7046dupTGGAAC(p.Thr2349_Ile2350insGlyThr) variant causes a disruptive inframe insertion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,222 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (no stars).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )
Consequence
FAT4
NM_001291303.3 disruptive_inframe_insertion
NM_001291303.3 disruptive_inframe_insertion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 7.96
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):
- FAT4-related neurodevelopmental disorderInheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
- Hennekam lymphangiectasia-lymphedema syndrome 2Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
- van Maldergem syndrome 2Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
- multiple congenital anomalies/dysmorphic syndrome-intellectual disabilityInheritance: AR Classification: STRONG Submitted by: Ambry Genetics
- Hennekam syndromeInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
- van Maldergem syndromeInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
Genome browser will be placed here
ACMG classification
Classification was made for transcript
Our verdict: Likely_pathogenic. The variant received 6 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PM4
Nonframeshift variant in NON repetitive region in NM_001291303.3.
PP3
No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
PP5
Variant 4-125434258-G-GACTGGA is Pathogenic according to our data. Variant chr4-125434258-G-GACTGGA is described in ClinVar as Pathogenic. ClinVar VariationId is 156109.Status of the report is no_assertion_criteria_provided, 0 stars.
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
| Sel. | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| FAT4 | NM_001291303.3 | MANE Select | c.7041_7046dupTGGAAC | p.Thr2349_Ile2350insGlyThr | disruptive_inframe_insertion | Exon 8 of 18 | NP_001278232.1 | A0A6Q8JR05 | |
| FAT4 | NM_001438396.1 | c.7041_7046dupTGGAAC | p.Thr2349_Ile2350insGlyThr | disruptive_inframe_insertion | Exon 7 of 17 | NP_001425325.1 | |||
| FAT4 | NM_001291285.3 | c.7041_7046dupTGGAAC | p.Thr2349_Ile2350insGlyThr | disruptive_inframe_insertion | Exon 8 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.7041_7046dupTGGAAC | p.Thr2349_Ile2350insGlyThr | disruptive_inframe_insertion | Exon 8 of 18 | ENSP00000377862.4 | A0A6Q8JR05 | |
| FAT4 | ENST00000335110.5 | TSL:1 | c.1935_1940dupTGGAAC | p.Thr647_Ile648insGlyThr | disruptive_inframe_insertion | Exon 7 of 15 | ENSP00000335169.5 | Q6V0I7-2 | |
| FAT4 | ENST00000674496.2 | c.1812_1817dupTGGAAC | p.Thr606_Ile607insGlyThr | disruptive_inframe_insertion | Exon 7 of 17 | ENSP00000501473.2 | A0A7P0T1I0 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome AF: 6.85e-7 AC: 1AN: 1460222Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 726352 show subpopulations
GnomAD4 exome
AF:
AC:
1
AN:
1460222
Hom.:
Cov.:
31
AF XY:
AC XY:
1
AN XY:
726352
show subpopulations
African (AFR)
AF:
AC:
0
AN:
33448
American (AMR)
AF:
AC:
0
AN:
44482
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
26082
East Asian (EAS)
AF:
AC:
0
AN:
39628
South Asian (SAS)
AF:
AC:
0
AN:
85978
European-Finnish (FIN)
AF:
AC:
0
AN:
53348
Middle Eastern (MID)
AF:
AC:
0
AN:
5760
European-Non Finnish (NFE)
AF:
AC:
1
AN:
1111174
Other (OTH)
AF:
AC:
0
AN:
60322
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.525
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome
GnomAD4 genome
Cov.:
32
ClinVar
ClinVar submissions as Germline
View on ClinVar Significance:Pathogenic
Revision:no assertion criteria provided
Pathogenic
VUS
Benign
Condition
1
-
-
Hennekam lymphangiectasia-lymphedema syndrome 2 (1)
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
PhyloP100
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
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