1-209786269-G-T

Position:

• chr1-209786269-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006147.4(IRF6):​c.*2151C>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.229 in 152,112 control chromosomes in the GnomAD database, including 4,643 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (4643 hom., cov: 32)
  • Exomes 𝑓: 0.13 (0 hom.)
• Consequence: IRF6 NM_006147.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.306

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 1-209786269-G-T is Benign according to our data. Variant chr1-209786269-G-T is described in ClinVar as [Benign]. Clinvar id is 295175.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.533 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IRF6	NM_006147.4	c.*2151C>A		3_prime_UTR_variant	9/9	ENST00000367021.8
IRF6	NM_001206696.2	c.*2151C>A		3_prime_UTR_variant	7/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IRF6	ENST00000367021.8	c.*2151C>A		3_prime_UTR_variant	9/9	1	NM_006147.4	P1
IRF6	ENST00000542854.5	c.*2151C>A		3_prime_UTR_variant	7/7	2
IRF6	ENST00000696134.1	c.*2982C>A		3_prime_UTR_variant, NMD_transcript_variant	9/9

Frequencies

GnomAD3 genomes AF: 0.229 AC: 34774 AN: 151978 Hom.: 4638 Cov.: 32

Gnomad AFR AF: 0.266

Gnomad AMI AF: 0.216

Gnomad AMR AF: 0.328

Gnomad ASJ AF: 0.133

Gnomad EAS AF: 0.550

Gnomad SAS AF: 0.311

Gnomad FIN AF: 0.141

Gnomad MID AF: 0.184

Gnomad NFE AF: 0.173

Gnomad OTH AF: 0.212

GnomAD4 exome AF: 0.125 AC: 2 AN: 16 Hom.: 0 Cov.: 0 AF XY: 0.0833 AC XY: 1 AN XY: 12

Gnomad4 FIN exome AF: 0.500

Gnomad4 NFE exome AF: 0.0833

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.229 AC: 34799 AN: 152096 Hom.: 4643 Cov.: 32 AF XY: 0.232 AC XY: 17282 AN XY: 74366

Gnomad4 AFR AF: 0.266

Gnomad4 AMR AF: 0.328

Gnomad4 ASJ AF: 0.133

Gnomad4 EAS AF: 0.550

Gnomad4 SAS AF: 0.311

Gnomad4 FIN AF: 0.141

Gnomad4 NFE AF: 0.173

Gnomad4 OTH AF: 0.210

Alfa AF: 0.185 Hom.: 4769

Bravo AF: 0.243

Asia WGS AF: 0.349 AC: 1215 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

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. -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	2.6
DANN	Benign	0.73

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1044516; hg19: chr1-209959614;