rs121434225
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_StrongPM2PP3PP5
The NM_006147.4(IRF6):c.1177C>T(p.Gln393Ter) variant causes a stop gained, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars).
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
IRF6
NM_006147.4 stop_gained, splice_region
NM_006147.4 stop_gained, splice_region
Scores
5
1
1
Splicing: ADA: 0.9981
2
Clinical Significance
Conservation
PhyloP100: 9.11
Genes affected
IRF6 (HGNC:6121): (interferon regulatory factor 6) This gene encodes a member of the interferon regulatory transcription factor (IRF) family. Family members share a highly-conserved N-terminal helix-turn-helix DNA-binding domain and a less conserved C-terminal protein-binding domain. The encoded protein may be a transcriptional activator. Mutations in this gene can cause van der Woude syndrome and popliteal pterygium syndrome. Mutations in this gene are also associated with non-syndromic orofacial cleft type 6. Alternate splicing results in multiple transcript variants.[provided by RefSeq, May 2011]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
PVS1
?
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 13 pathogenic variants in the truncated region.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
PP5
?
Variant 1-209789669-G-A is Pathogenic according to our data. Variant chr1-209789669-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 3413.Status of the report is no_assertion_criteria_provided, 0 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
IRF6 | NM_006147.4 | c.1177C>T | p.Gln393Ter | stop_gained, splice_region_variant | 8/9 | ENST00000367021.8 | |
IRF6 | NM_001206696.2 | c.892C>T | p.Gln298Ter | stop_gained, splice_region_variant | 6/7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
IRF6 | ENST00000367021.8 | c.1177C>T | p.Gln393Ter | stop_gained, splice_region_variant | 8/9 | 1 | NM_006147.4 | P1 | |
IRF6 | ENST00000542854.5 | c.892C>T | p.Gln298Ter | stop_gained, splice_region_variant | 6/7 | 2 | |||
IRF6 | ENST00000643798.1 | c.*687C>T | splice_region_variant, 3_prime_UTR_variant, NMD_transcript_variant | 8/9 | |||||
IRF6 | ENST00000696134.1 | c.*604C>T | splice_region_variant, 3_prime_UTR_variant, NMD_transcript_variant | 8/9 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1453032Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0AN XY: 723528
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
AC:
0
AN:
1453032
Hom.:
Cov.:
29
AF XY:
AC XY:
0
AN XY:
723528
Gnomad4 AFR exome
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GnomAD4 genome ? Cov.: 33
GnomAD4 genome
?
Cov.:
33
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link
Submissions by phenotype
Popliteal pterygium syndrome Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Oct 01, 2002 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
MutationTaster
Benign
A;A
Vest4
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at