chr1-209788455-TG-T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PVS1_ModeratePM2

The NM_006147.4(IRF6):​c.1368delC​(p.Ser457AlafsTer34) 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 Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

IRF6
NM_006147.4 frameshift

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.52

Publications

0 publications found
Variant links:
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]
IRF6 Gene-Disease associations (from GenCC):
  • autosomal dominant popliteal pterygium syndrome
    Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae)
  • IRF6-related condition
    Inheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics
  • van der Woude syndrome 1
    Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
  • popliteal pterygium syndrome
    Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics
  • tooth agenesis
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • van der Woude syndrome
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • orofacial cleft 6, susceptibility to
    Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0256 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
IRF6NM_006147.4 linkc.1368delC p.Ser457AlafsTer34 frameshift_variant Exon 9 of 9 ENST00000367021.8 NP_006138.1 O14896-1G0Z349
IRF6NM_001206696.2 linkc.1083delC p.Ser362AlafsTer34 frameshift_variant Exon 7 of 7 NP_001193625.1 O14896-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
IRF6ENST00000367021.8 linkc.1368delC p.Ser457AlafsTer34 frameshift_variant Exon 9 of 9 1 NM_006147.4 ENSP00000355988.3 O14896-1
ENSG00000289700ENST00000696133.1 linkc.1368delC p.Ser457AlafsTer92 frameshift_variant Exon 9 of 10 ENSP00000512426.1 A0A8Q3SJ75

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
0.00
AC:
0
AN:
1458686
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
725894
African (AFR)
AF:
0.00
AC:
0
AN:
33426
American (AMR)
AF:
0.00
AC:
0
AN:
44718
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26114
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39680
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86192
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53292
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5688
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
1109322
Other (OTH)
AF:
0.00
AC:
0
AN:
60254
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Popliteal pterygium syndrome;C1837213:Orofacial cleft 6, susceptibility to;C4551864:Van der Woude syndrome 1 Uncertain:1
Oct 18, 2017
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change deletes 1 nucleotide in exon 9 of the IRF6 mRNA (c.1368delC), causing a frameshift at codon 457. This is not anticipated to result in nonsense mediated decay but it is expected to expected to alter the last 11 amino acids and extend the IRF6 protein by an additional 22 amino acids (p.Ser457Alafs*34). This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with IRF6-related disease. Experimental studies and prediction algorithms are not available for this variant, and the functional significance of the disrupted amino acids is currently unknown. Multiple downstream frameshift variants that results in an extended protein product have been reported in individuals affected with van der Woude syndrome (PMID: PMID: 12219090, 23154523, 19282774). However these variants create a frameshifts and extensions that are different from the one created by this variant. Therefore the effect of this particular frameshift and extension is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
PhyloP100
-1.5

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

Publications

Other links and lift over

dbSNP: rs1553247577; hg19: chr1-209961800; API