chr4-125446297-A-G
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Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_ModeratePM2PP3_Strong
The ENST00000335110.5(FAT4):c.2094-2A>G variant causes a splice acceptor change. The variant allele was found at a frequency of 0.000013 in 1,612,180 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000014 ( 0 hom. )
Consequence
FAT4
ENST00000335110.5 splice_acceptor
ENST00000335110.5 splice_acceptor
Scores
3
1
3
Splicing: ADA: 0.9997
1
Clinical Significance
Not reported in ClinVar
Conservation
PhyloP100: 5.65
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
PVS1
Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.025235288 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;
PP3
BayesDel_addAF computational evidence supports a deleterious effect, 0.487
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FAT4 | NM_001291303.3 | c.7204A>G | p.Arg2402Gly | missense_variant | 9/18 | ENST00000394329.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FAT4 | ENST00000335110.5 | c.2094-2A>G | splice_acceptor_variant | 1 | |||||
FAT4 | ENST00000394329.9 | c.7204A>G | p.Arg2402Gly | missense_variant | 9/18 | 5 | NM_001291303.3 | P1 | |
FAT4 | ENST00000674496.2 | c.1975A>G | p.Arg659Gly | missense_variant | 8/17 | ||||
FAT4 | ENST00000509444.1 | n.187A>G | non_coding_transcript_exon_variant | 1/2 | 3 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152166Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000400 AC: 10AN: 250136Hom.: 0 AF XY: 0.0000444 AC XY: 6AN XY: 135244
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GnomAD4 exome AF: 0.0000137 AC: 20AN: 1460014Hom.: 0 Cov.: 30 AF XY: 0.0000138 AC XY: 10AN XY: 726236
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GnomAD4 genome AF: 0.00000657 AC: 1AN: 152166Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74348
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ClinVar
Not reported inComputational scores
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Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Benign
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
MutationTaster
Benign
D;D
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Splicing
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dbscSNV1_ADA
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_AL_spliceai
Position offset: 2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at