rs599021

chr1-209787577-A-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_006147.4(IRF6):c.*843T>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.363 in 152,048 control chromosomes in the GnomAD database, including 10,697 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.36 (10687 hom., cov: 31)
  • Exomes 𝑓: 0.32 (10 hom.)
• Consequence: IRF6 NM_006147.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 0.266

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 1-209787577-A-C is Benign according to our data. Variant chr1-209787577-A-C is described in ClinVar as [Benign]. Clinvar id is 295189.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.429 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IRF6	NM_006147.4	c.*843T>G		3_prime_UTR_variant	9/9	ENST00000367021.8
IRF6	NM_001206696.2	c.*843T>G		3_prime_UTR_variant	7/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IRF6	ENST00000367021.8	c.*843T>G		3_prime_UTR_variant	9/9	1	NM_006147.4	P1
IRF6	ENST00000542854.5	c.*843T>G		3_prime_UTR_variant	7/7	2
IRF6	ENST00000696134.1	c.*1674T>G		3_prime_UTR_variant, NMD_transcript_variant	9/9

Frequencies

GnomAD3 genomes AF: 0.363 AC: 55075 AN: 151750 Hom.: 10686 Cov.: 31

Gnomad AFR AF: 0.261

Gnomad AMI AF: 0.467

Gnomad AMR AF: 0.302

Gnomad ASJ AF: 0.520

Gnomad EAS AF: 0.241

Gnomad SAS AF: 0.353

Gnomad FIN AF: 0.394

Gnomad MID AF: 0.440

Gnomad NFE AF: 0.433

Gnomad OTH AF: 0.407

GnomAD4 exome AF: 0.322 AC: 58 AN: 180 Hom.: 10 Cov.: 0 AF XY: 0.329 AC XY: 46 AN XY: 140

Gnomad4 AFR exome AF: 0.417

Gnomad4 AMR exome AF: 0.00

Gnomad4 EAS exome AF: 0.125

Gnomad4 FIN exome AF: 0.227

Gnomad4 NFE exome AF: 0.393

Gnomad4 OTH exome AF: 0.136

GnomAD4 genome AF: 0.363 AC: 55098 AN: 151868 Hom.: 10687 Cov.: 31 AF XY: 0.359 AC XY: 26647 AN XY: 74206

Gnomad4 AFR AF: 0.261

Gnomad4 AMR AF: 0.301

Gnomad4 ASJ AF: 0.520

Gnomad4 EAS AF: 0.242

Gnomad4 SAS AF: 0.353

Gnomad4 FIN AF: 0.394

Gnomad4 NFE AF: 0.433

Gnomad4 OTH AF: 0.408

Alfa AF: 0.398 Hom.: 3393

Bravo AF: 0.349

Asia WGS AF: 0.318 AC: 1104 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

Orofacial cleft 6, susceptibility to Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This 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 submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
Cadd	Benign	4.1
Dann	Benign	0.64

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

Other links and lift over

dbSNP: rs599021; hg19: chr1-209960922;