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rs61099902

chr1-209789693-A-Gchr1-209789693-A-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_006147.4(IRF6):c.1153T>C(p.Leu385=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0041 in 1,613,494 control chromosomes in the GnomAD database, including 188 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.019 ( 83 hom., cov: 33)
Exomes 𝑓: 0.0025 ( 105 hom. )

Consequence

IRF6
NM_006147.4 synonymous

Scores

2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.438
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4
?
    BP4 - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
Computational evidence support a benign effect (BayesDel_noAF=-0.82).
BP6
?
    BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 1-209789693-A-G is Benign according to our data. Variant chr1-209789693-A-G is described in ClinVar as [Benign]. Clinvar id is 259922.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP7
?
    BP7 - A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved
Synonymous conserved (PhyloP=0.438 with no splicing effect.
BA1
?
    BA1 - Allele frequency is >5% in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium
GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0638 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
IRF6NM_006147.4 linkuse as main transcriptc.1153T>C p.Leu385= synonymous_variant 8/9 ENST00000367021.8
IRF6NM_001206696.2 linkuse as main transcriptc.868T>C p.Leu290= synonymous_variant 6/7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
IRF6ENST00000367021.8 linkuse as main transcriptc.1153T>C p.Leu385= synonymous_variant 8/91 NM_006147.4 P1O14896-1
IRF6ENST00000542854.5 linkuse as main transcriptc.868T>C p.Leu290= synonymous_variant 6/72 O14896-2
IRF6ENST00000643798.1 linkuse as main transcriptc.*663T>C 3_prime_UTR_variant, NMD_transcript_variant 8/9
IRF6ENST00000696134.1 linkuse as main transcriptc.*580T>C 3_prime_UTR_variant, NMD_transcript_variant 8/9

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.0193
AC:
2936
AN:
152130
Hom.:
83
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0658
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00530
Gnomad ASJ
AF:
0.0219
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000414
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00316
Gnomad NFE
AF:
0.000441
Gnomad OTH
AF:
0.0100
GnomAD3 exomes
AF:
0.00568
AC:
1429
AN:
251484
Hom.:
48
AF XY:
0.00434
AC XY:
590
AN XY:
135916
show subpopulations
Gnomad AFR exome
AF:
0.0641
Gnomad AMR exome
AF:
0.00312
Gnomad ASJ exome
AF:
0.0192
Gnomad EAS exome
AF:
0.0000544
Gnomad SAS exome
AF:
0.000621
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000413
Gnomad OTH exome
AF:
0.00293
GnomAD4 exome
AF:
0.00251
AC:
3674
AN:
1461246
Hom.:
105
Cov.:
30
AF XY:
0.00231
AC XY:
1681
AN XY:
726990
show subpopulations
Gnomad4 AFR exome
AF:
0.0688
Gnomad4 AMR exome
AF:
0.00340
Gnomad4 ASJ exome
AF:
0.0205
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.000789
Gnomad4 FIN exome
AF:
0.0000187
Gnomad4 NFE exome
AF:
0.000215
Gnomad4 OTH exome
AF:
0.00596
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.0193
AC:
2945
AN:
152248
Hom.:
83
Cov.:
33
AF XY:
0.0190
AC XY:
1412
AN XY:
74438
show subpopulations
Gnomad4 AFR
AF:
0.0658
Gnomad4 AMR
AF:
0.00529
Gnomad4 ASJ
AF:
0.0219
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000414
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000441
Gnomad4 OTH
AF:
0.00994
Alfa
AF:
0.00941
Hom.:
11
Bravo
AF:
0.0216
Asia WGS
AF:
0.00260
AC:
9
AN:
3478
EpiCase
AF:
0.000763
EpiControl
AF:
0.000415

ClinVar

Significance: Benign
Submissions summary: Benign:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:1
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact Sciences-- -
Van der Woude syndrome;C0265259:Popliteal pterygium syndrome;C1837213:Orofacial cleft 6, susceptibility to Benign:1
Benign, criteria provided, single submitterclinical testingInvitaeJan 18, 2024- -
Orofacial cleft 6, susceptibility to Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Van der Woude syndrome 1 Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
not provided Benign:1
Benign, criteria provided, single submitterclinical testingGeneDxMar 03, 2015- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.82
Cadd
Benign
7.9
Dann
Benign
0.73

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs61099902; hg19: chr1-209963038; API