chr1-209793498-A-G

Variant names:

• chr1-209793498-A-G
• rs595918
• NM_006147.4:c.509-1071T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_006147.4(IRF6):​c.509-1071T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.817 in 152,164 control chromosomes in the GnomAD database, including 50,819 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.82 (50819 hom., cov: 32)
• Consequence: IRF6 NM_006147.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0410
• Publications: 6 publications found

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]

IRF6 Gene-Disease associations (from GenCC):

• autosomal dominant popliteal pterygium syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae)
• IRF6-related condition

  Inheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics
• van der Woude syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• popliteal pterygium syndrome

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics
• tooth agenesis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• van der Woude syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• orofacial cleft 6, susceptibility to

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ENSG00000289700 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.842 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006147.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IRF6	NM_006147.4	MANE Select	c.509-1071T>C		intron	N/A	NP_006138.1
	IRF6	NM_001206696.2		c.224-1071T>C		intron	N/A	NP_001193625.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IRF6	ENST00000367021.8	TSL:1 MANE Select	c.509-1071T>C		intron	N/A	ENSP00000355988.3
	ENSG00000289700	ENST00000696133.1		c.509-1071T>C		intron	N/A	ENSP00000512426.1
	IRF6	ENST00000542854.5	TSL:2	c.224-1071T>C		intron	N/A	ENSP00000440532.1

Frequencies

GnomAD3 genomes AF: 0.817 AC: 124191 AN: 152046 Hom.: 50787 Cov.: 32

Gnomad AFR AF: 0.849

Gnomad AMI AF: 0.862

Gnomad AMR AF: 0.832

Gnomad ASJ AF: 0.841

Gnomad EAS AF: 0.808

Gnomad SAS AF: 0.780

Gnomad FIN AF: 0.759

Gnomad MID AF: 0.816

Gnomad NFE AF: 0.804

Gnomad OTH AF: 0.829

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.817 AC: 124277 AN: 152164 Hom.: 50819 Cov.: 32 AF XY: 0.814 AC XY: 60556 AN XY: 74410

African (AFR) AF: 0.849 AC: 35224 AN: 41480

American (AMR) AF: 0.832 AC: 12728 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.841 AC: 2919 AN: 3472

East Asian (EAS) AF: 0.808 AC: 4191 AN: 5184

South Asian (SAS) AF: 0.780 AC: 3765 AN: 4826

European-Finnish (FIN) AF: 0.759 AC: 8039 AN: 10586

Middle Eastern (MID) AF: 0.827 AC: 243 AN: 294

European-Non Finnish (NFE) AF: 0.804 AC: 54641 AN: 68000

Other (OTH) AF: 0.825 AC: 1741 AN: 2110

Alfa AF: 0.807 Hom.: 10028

Bravo AF: 0.821

Asia WGS AF: 0.760 AC: 2643 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	8.8
DANN	Benign	0.59
PhyloP100		0.041
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs595918; hg19: chr1-209966843;