chr1-209786527-G-A

Position:

• chr1-209786527-G-A

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.*1893C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.809 in 152,042 control chromosomes in the GnomAD database, including 49,787 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.81 (49784 hom., cov: 30)
  • Exomes 𝑓: 0.75 (3 hom.)
• Consequence: IRF6 NM_006147.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.0200

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=-0.93).
• BP6: Variant 1-209786527-G-A is Benign according to our data. Variant chr1-209786527-G-A is described in ClinVar as [Benign]. Clinvar id is 295178.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.84 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IRF6	NM_006147.4	c.*1893C>T		3_prime_UTR_variant	9/9	ENST00000367021.8
IRF6	NM_001206696.2	c.*1893C>T		3_prime_UTR_variant	7/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IRF6	ENST00000367021.8	c.*1893C>T		3_prime_UTR_variant	9/9	1	NM_006147.4	P1
IRF6	ENST00000542854.5	c.*1893C>T		3_prime_UTR_variant	7/7	2
IRF6	ENST00000696134.1	c.*2724C>T		3_prime_UTR_variant, NMD_transcript_variant	9/9

Frequencies

GnomAD3 genomes AF: 0.809 AC: 122861 AN: 151916 Hom.: 49753 Cov.: 30

Gnomad AFR AF: 0.847

Gnomad AMI AF: 0.863

Gnomad AMR AF: 0.827

Gnomad ASJ AF: 0.829

Gnomad EAS AF: 0.806

Gnomad SAS AF: 0.780

Gnomad FIN AF: 0.742

Gnomad MID AF: 0.816

Gnomad NFE AF: 0.792

Gnomad OTH AF: 0.819

GnomAD4 exome AF: 0.750 AC: 6 AN: 8 Hom.: 3 Cov.: 0 AF XY: 0.667 AC XY: 4 AN XY: 6

Gnomad4 AFR exome AF: 1.00

Gnomad4 NFE exome AF: 0.667

GnomAD4 genome AF: 0.809 AC: 122947 AN: 152034 Hom.: 49784 Cov.: 30 AF XY: 0.806 AC XY: 59898 AN XY: 74306

Gnomad4 AFR AF: 0.847

Gnomad4 AMR AF: 0.826

Gnomad4 ASJ AF: 0.829

Gnomad4 EAS AF: 0.806

Gnomad4 SAS AF: 0.780

Gnomad4 FIN AF: 0.742

Gnomad4 NFE AF: 0.792

Gnomad4 OTH AF: 0.816

Alfa AF: 0.806 Hom.: 16253

Bravo AF: 0.814

Asia WGS AF: 0.756 AC: 2632 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 12, 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 12, 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

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- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	3.0
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: rs680331; hg19: chr1-209959872;