1-209789693-A-G

Position:

• chr1-209789693-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.438

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: 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: Synonymous conserved (PhyloP=0.438 with no splicing effect.
• BA1: 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	Protein	UniProt
IRF6	NM_006147.4	c.1153T>C	p.Leu385=	synonymous_variant	8/9	ENST00000367021.8	NP_006138.1
IRF6	NM_001206696.2	c.868T>C	p.Leu290=	synonymous_variant	6/7		NP_001193625.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IRF6	ENST00000367021.8	c.1153T>C	p.Leu385=	synonymous_variant	8/9	1	NM_006147.4	ENSP00000355988	P1
IRF6	ENST00000542854.5	c.868T>C	p.Leu290=	synonymous_variant	6/7	2		ENSP00000440532
IRF6	ENST00000643798.1	c.*663T>C		3_prime_UTR_variant, NMD_transcript_variant	8/9			ENSP00000496669
IRF6	ENST00000696134.1	c.*580T>C		3_prime_UTR_variant, NMD_transcript_variant	8/9			ENSP00000512427

Frequencies

GnomAD3 genomes AF: 0.0193 AC: 2936 AN: 152130 Hom.: 83 Cov.: 33

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

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

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 AF: 0.0193 AC: 2945 AN: 152248 Hom.: 83 Cov.: 33 AF XY: 0.0190 AC XY: 1412 AN XY: 74438

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:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Van der Woude syndrome;C0265259:Popliteal pterygium syndrome;C1837213:Orofacial cleft 6, susceptibility to Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 18, 2024

- -

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	-0.82
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

Other links and lift over

dbSNP: rs61099902; hg19: chr1-209963038;